INHIBITORS OF FACTOR Xa AND OTHER SERINE PROTEASES INVOLVED IN THE COAGULATION CASCADE

ABSTRACT

Compounds useful as intermediates for synthesis of compounds of Formula (1):  
                 
 
wherein A, B, C, G, and W 1  have any of the values defined in the specification.

This application is a divisional of U.S. Ser. No. 11/017598 filed Dec.20, 2004, which is a divisional of U.S. Ser. No. 10/278,643 filed Oct.23, 2002, now U.S. Pat. No. 7,030,141, which claims the benefit of U.S.Provisional application 60/334,168, filed Nov. 29, 2001, and of U.S.Provisional application 60/384,895, filed May 31, 2002.

FIELD OF THE INVENTION

The present invention relates to cyclic amino acid and prolinederivatives which display inhibitory effects of the serine proteasefactor Xa. The invention also discloses pharmaceutically acceptablesalts of the compounds, pharmaceutically acceptable compositionscomprising the compounds or their salts, and methods of using them astherapeutic agents for treating or preventing disease states in mammalscharacterized by abnormal thrombosis.

BACKGROUND OF THE INVENTION

In economically developed countries, cardiovascular disease represents amajor cause of mortality. In particular, abnormal coagulation andinappropriate thrombus formation within blood vessels precipitates manyacute cardiovascular disease states. While it has long been recognizedthat a variety of plasma proteins such as fibrinogen, serine proteases,and cellular receptors are involved in hemostasis, it is abnormalregulation that has emerged as important contributing factors tocardiovascular disease.

Thrombin can be considered the key or principal regulatory enzyme in thecoagulation cascade; it serves a pluralistic role as both a positive andnegative feedback regulator in normal hemostasis. However, in somepathologic conditions, the positive feedback regulation is amplifiedthrough catalytic activation of cofactors required for thrombingeneration. Such cofactors include factor Xa, a serine protease whichoccupies a pivotal position in the coagulation cascade. Factor X is thezymogen of factor Xa. Factor X can be activated either the intrinsic orextrinsic pathways of the coagulation system. Initiation of coagulationby either pathway in response to vascular injury activates factor X tofactor Xa. Factor Xa and its cofactor, factor Va, combine on aphospholipid membrane to form the “prothombinase” complex, whichactivates prothrombin to thrombin. Thrombin cleaves fibrinogen tofibrin, activates platelets, and converts factor XIII to XIIIa which isthe principal enzyme involved in thrombus generation, growth, andstabilization. Accordingly, the location of the prothrombinase complexat the convergence of both the intrinsic and extrinsic coagulationpathways suggests that inhibition of factor Xa, and hence thrombingeneration, may be a viable approach to limiting the procoagulantactivity of thrombin.

Evidence exists for the role of factor Xa inhibitors as anticoagulants.Antistasin, a potent inhibitor of blood coagulation factor Xa from theMexican leech, Haementeria officinalis, displays antithrombotic activityin various models of arterial and venous thrombosis (Lapatto et al.,Embo. J, 1997:5151-5161). Other protein or polypeptide factor Xainhibitors include recombinant tick anticoagulant peptide (rTAP), whichis known to accelerate the recombinant tissue plasminogen activatormediated clot lysis and prevent acute reocclusion in the dog, henceindicating factor Xa inhibitors may be useful as an adjunct tothrombolytic therapy (Mellott et al., Fibrinolysis, 1993: 195-202).Furthermore, in a canine coronary artery electrolytic lesion model, rTAPwas demonstrated to reduce thrombus mass and time to occlusion in theabsence of dramatic hemodynamic or hemostatic changes indicating theprimary role for factor Xa in the process of arterial thrombosis (Lynchet al., Thromb. Haemostasis, 1995:640-645; Schaffer et al., Circulation,1991: 1741-1748). On the venous side, rTAP was also demonstrated toreduce fibrin deposition in a rabbit model of venous thrombosis whilehaving little affect on systemic hemostatic parameters (Fioravanti etal., Thromb. Res., 1993: 317-324). In addition to these relatively highmolecular weight proteins that are not suitable as oral antithromboticagents, there also exist examples of low molecular weight factor Xainhibitors. In particular DX9065a, a low molecular weight syntheticfactor Xa inhibitor, has also shown antithrombotic potential in variousexperimental thrombosis rat models. In both arteriovenous shunt andvenous stasis models, inhibition of thrombus formation was achieved atdoses that had little effect on APTT, indicating that DX9065a iseffective in preventing thrombosis and hence has therapeuticantithrombotic potential (Wong et al., Thromb. Res., 1996: 117-126).

Recently, it has been appreciated that factor Xa inhibition may providesustained antithrombotic protection. Specifically, several animalstudies show that inhibition of short term exposure to factor Xaproduces a sustained antithrombotic. (Leadley, Curr. Top. Med. Chem.,2001: v. 1, 151-159.) Finally, the article by Leadley observes thatfactor Xa inhibition potentially provides a large therapeutical windowbetween antithrombotic efficacy and bleeding tendency. Consequently,there may exist a range in which factor Xa inhibition is achievedwithout an concurrent increase in a patients susceptibility to bleeding.

The majority of factor Xa inhibitors known to date have been summarizedin two reviews (Edmunds et al., Annual Reports in Medicinal Chemistry,1996:51 and Kunitada and Nagahara, Curr. Pharm. Des., 1996:531-542).However, it is readily apparent that there still exists a need for moreeffective agents that regulate factor Xa proteolytic activity.

SUMMARY OF THE INVENTION

These and other needs are met by the present invention which is directedto a compound of Formula I

or a pharmaceutically acceptable salt thereof wherein:

A is aryl or substituted aryl or monocyclic heteroaryl or substitutedmonocyclic heteroaryl;

(C₃-C₇)cycloalkyl, (C₃-C₇)heterocycloalkyl, (C₄-C₇)cycloalkenyl,(C₄-C₇)heterocycloalkenyl, aryl, or heteroaryl, any of which may beoptionally substituted by halo, (C₁-C₆)alkyl, or halo(C₁-C₆)alkyl,(C₁-C₆)alkoxy, —CN, haloalkyl, amino, alkylamino, amidino, amido, orsulfonamido;

C is phenyl or heteroaryl, wherein phenyl or heteroaryl is optionallysubstituted with one or more substituents selected from halogen,hydroxy, —CO₂R², —COR², —CONR²R^(2′), alkoxy, alkyl, —CN, haloalkyl,amino, alkylamino, amidino, amido, or sulfonamido;

G is H, halo, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,

-   -   —CH₂O—(C₁-C₆)alkyl, —CH₂—CO₂(C₁-C₆)alkyl, —CH₂—NR2R2′, or        —CH₂—CONH(C₁-C₆)alkyl;

W¹ is a saturated or unsaturated, substituted or unsubstitutedhydrocarbon chain or hydrocarbon-heteroatom chain having from 2 to 6atoms, wherein W¹ connects the nitrogen atom at position 1 to the carbonatom at position 2 to form a four to eight membered ring;

R¹ is (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl, (C₃-C₇)heterocycloalkyl,(C₄-C₇)cycloalkenyl, (C₄-C₇)heterocycloalkenyl, aryl, monocyclicheteroaryl, or —NR³R⁴;

R² and R^(2′) are each independently H or (C₁-C₆)alkyl; and

R³ and R⁴ are each independently H, (C₁-C₆)alkyl, aralkyl, aryl,monocyclic heteroaryl, alkoxycarbonyl, aralkoxycarbonyl, —SO₂alkyl, orjoined together to form a saturated or unsaturated 3 to 7 membered ring.

The invention is also directed to a compound of formula II:

or a pharmaceutically acceptable salt thereof wherein

“ - - - ” is a bond or is absent;

X^(II) is CH₂, CH, NH or N;

R¹⁰ and R¹¹ are each independently H, —OH, halo, alkyl, haloalkyl,—NR⁸R⁹, —OR², —CN, —CH₂OH, —CH₂—NR³R⁴, aryl, monocyclic heteroaryl,alkylaryl, —CH═O, —CH₂OR², —COR², —CO₂R², or —CONR³R⁴ or are takentogether to form ═O, ═NOR², ═C(C₁-C₆alkyl)₂, or ═CR²H, with the provisothat when “ - - - ” is a bond, R¹¹ is absent, and X^(II) is CH or N, andR¹⁰ is H, —OH, halo, alkyl, haloalkyl, —NR⁸R⁹, —OR², —CN, —CH₂OH,—CH₂—NR³R⁴, aryl, monocyclic heteroaryl, alkylaryl, —CH═O, —CH₂OR²,—COR², —CO₂R², or —CONR³R⁴;

A is aryl and substituted aryl or monocyclic heteroaryl or substitutedmonocyclic heteroaryl;

(C₃-C₇)cycloalkyl, (C₃-C₇)heterocycloalkyl, (C₄-C₇)cycloalkenyl,(C₄-C₇)heterocycloalkenyl, aryl, or heteroaryl, any of which may beoptionally substituted;

C is phenyl or heteroaryl, wherein phenyl or heteroaryl is optionallysubstituted with one or more substituents selected from halogen,hydroxy, —CO₂R², —COR², —CONR²R^(2′), alkoxy, alkyl, —CN, haloalkyl,amino, alkylamino, amidino, amido, or sulfonamido;

G is H, halo, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,

—CH₂O—(C₁-C₆)alkyl, —CH₂—CO₂(C₁-C₆)alkyl, —CH₂—NR²R²′, or—CH₂—CONH(C₁-C₆)alkyl;or —CH₂—CONH(C₁-C₆)alkyl;

R¹ is (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl, (C₃-C₇)heterocycloalkyl,(C₄-C₇)cycloalkenyl, (C₄-C₇)heterocycloalkenyl, aryl, monocyclicheteroaryl, or —NR³R⁴;

R² and R^(2′) are each independently H or (C₁-C₆)alkyl; and

R³ and R⁴ are independently H, (C₁-C₆)alkyl, aralkyl, aryl, monocyclicheteroaryl, alkoxycarbonyl, aralkoxycarbonyl, —SO₂alkyl, or joinedtogether to form a saturated or unsaturated 5 to 7 membered ring.

The invention is also directed to a compound of Formula III

or a pharmaceutically acceptable salt thereof wherein

is a bond or is absent;

Z is C—H, C-halo, C—(C₁-C₆)alkyl, C-halo(C₁-C₆)alkyl, C—(C₁-C₆)alkoxy,or N;

X^(II) is CH₂,CH, NH or N;

R¹⁰ and R¹¹ are each independently H, —OH, halo, alkyl, haloalkyl,—NR⁸R⁹, —OR², —CN, —CH₂OH, —CH₂—NR³R⁴, aryl, monocyclic heteroaryl,alkylaryl, —CH═O, —CH₂OR², —COR², —CO₂R², or —CONR³R⁴ or are takentogether to form ═O, ═NOR², ═C(C₁-C₆alkyl)₂, or ═CR²H, with the provisothat when “ - - - ” is a bond, R¹¹ is absent, and X^(II) is CH or N, andR¹⁰ is H, —OH, halo, alkyl, haloalkyl, —NR⁸R⁹, —OR², —CN, —CH₂OH,—CH₂—NR³R⁴, aryl, monocyclic heteroaryl, alkylaryl, —CH═O, —CH₂OR²,—COR², —CO₂R², or —CONR³R⁴;

A is aryl and substituted aryl or monocyclic heteroaryl or substitutedmonocyclic heteroaryl;

(C₃-C₇)cycloalkyl, (C₃-C₇)heterocycloalkyl, (C₄-C₇)cycloalkenyl,(C₄-C₇)heterocycloalkenyl, aryl, or heteroaryl, any of which may beoptionally substituted, wherein R¹ is (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl,(C₃-C₇)heterocycloalkyl, (C₄-C₇)cycloalkenyl, (C₄-C₇)heterocycloalkenyl,aryl, monocyclic heteroaryl, or —NR³R⁴;

G is H, halo, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,

-   -   —CH₂O—(C₁-C₆)alkyl, —CH₂—CO₂(C₁-C₆)alkyl, —CH₂—CONH₂, or        —CH₂—CONH(C₁-C₆)alkyl;

R² and R^(2′) are each independently H or (C₁-C₆)alkyl; and

R³ and R⁴ are independently H, (C₁-C₆)alkyl, aralkyl, aryl, monocyclicheteroaryl, alkoxycarbonyl, aralkoxycarbonyl, —SO₂alkyl, or joinedtogether to form a saturated or unsaturated 5 to 7 membered ring; and

R¹² and R¹³ are each independently H, halo, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, or (C₁-C₆)alkoxy.

What is also provided is a compound of Formula IV

or a pharmaceutically acceptable salt thereof wherein

is a bond or is absent;

Z is C—H, C-halo, C—(C₁-C₆)alkyl, C-halo(C₁-C₆)alkyl, C—(C₁-C₆)alkoxy,or N;

X^(II) is CH₂, CH, NH or N;

R¹⁰ and R¹¹ are each independently H, —OH, halo, alkyl, haloalkyl,—NR⁸R⁹, —OR², —CN, —CH₂OH, —CH₂—NR³R⁴, aryl, monocyclic heteroaryl,alkylaryl, —CH═O, —CH₂OR², —COR², —CO₂R², or —CONR³R⁴ or are takentogether to form ═O, ═NOR², ═C(C₁-C₆alkyl)₂, or ═CR²H, with the provisothat when “ - - - ” is a bond, R¹¹ is absent, and X^(II) is CH or N, andR¹⁰ is H, —OH, halo, alkyl, haloalkyl, —NR⁸R⁹, —OR², —CN, —CH₂OH,—CH₂—NR³R⁴, aryl, monocyclic heteroaryl, alkylaryl, —CH═O, —CH₂OR²,—COR², —CO₂R², or —CONR³R⁴;

(C₃-C₇)cycloalkyl, (C₃-C₇)heterocycloalkyl, (C₄-C₇)cycloalkenyl,(C₄-C₇)heterocycloalkenyl, aryl, or heteroaryl, any of which may beoptionally substituted, wherein R¹ is (C₁-C₆)alkoxy, (C₃-C₇)cycloalkyl,(C₃-C₇)heterocycloalkyl, (C₄-C₇)cycloalkenyl, (C₄-C₇)heterocycloalkenyl,aryl, monocyclic heteroaryl, or —NR³R⁴;

G is H, halo, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,

—CH₂O—(C₁-C₆)alkyl, —CH₂—CO₂(C₁-C₆)alkyl, —CH₂—CONH₂, or—CH₂—CONH(C₁-C₆)alkyl;

R² and R^(2′) are each independently H or (C₁-C₆)alkyl; and

R³ and R⁴ are independently H, (C₁-C₆)alkyl, aralkyl, aryl, monocyclicheteroaryl, alkoxycarbonyl, aralkoxycarbonyl, —SO₂alkyl, or joinedtogether to form a saturated or unsaturated 5 to 7 membered ring;

R¹² and R¹³ are each independently H, halo, (C₁-C₆)alkyl, orhalo(C₁-C₆)alkyl, or (C₁-C₆)alkoxy;

R¹⁴ and R¹⁵ are each independently H, halo, alkyl, or haloalkyl, orNR⁸R⁹ wherein R⁸ and R⁹ are as defined for R³ and R⁴;

X and Y are each C, or one of X and Y is C and the other is N, providedthat when one of X or Y is N, R¹⁴ or R¹⁵ is absent at that position.

What is also provided is a compound of Formula V

or a pharmaceutically acceptable salt thereof wherein

is a bond or is absent;

Z is C—H, C-halo, C—(C₁-C₆)alkyl, C-halo(C₁-C₆)alkyl, C—(C₁-C₆)alkoxy,or N;

G is H, halo, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,

—CH₂O—(C₁-C₆)alkyl, —CH₂—CO₂(C₁-C₆)alkyl, —CH₂—CONH₂, or—CH₂—CONH(C₁-C₆)alkyl;

X^(II) is CH₂,CH, NH or N;

R¹⁰ and R¹¹ are each independently H, —OH, halo, alkyl, haloalkyl,—NR⁸R⁹, —OR², —CN, —CH₂OH, —CH₂—NR³R⁴, aryl, monocyclic heteroaryl,alkylaryl, —CH═O, —CH₂OR², —COR², —CO₂R², or —CONR³R⁴ or are takentogether to form ═O, ═NOR², ═C(C₁-C₆alkyl)₂, or ═CR²H, with the provisothat when “ - - - ” is a bond, R¹¹ is absent, and X^(II) is CH or N, andR¹⁰ is H, —OH, halo, alkyl, haloalkyl, —NR⁸R⁹, —OR², —CN, —CH₂OH,—CH₂—NR³R⁴, aryl, monocyclic heteroaryl, alkylaryl, —CH═O, —CH₂OR²,—COR², —CO₂R², or —CONR³R⁴;

R² is H or (C₁-C₆)alkyl; and

R³ and R⁴ are independently H, (C₁-C₆)alkyl, aralkyl, aryl, monocyclicheteroaryl, alkoxycarbonyl, aralkoxycarbonyl, —SO₂alkyl, or joinedtogether to form a saturated or unsaturated 5 to 7 membered ring;

R¹² and R¹³ are each independently H, halo, (C₁-C₆)alkyl, orhalo(C₁-C₆)alkyl, or (C₁-C₆)alkoxy;

R¹⁴ and R¹⁵ are each independently H, halo, alkyl, or haloalkyl, orNR⁸R⁹ wherein R⁸ and R⁹ are as defined for R³ and R⁴;

X and Y are each independently C or N, provided that when one of X or Yis N, R¹⁴ or R¹⁵ is absent at that position.

X′ and Y′ are each independently CH or N;

is absent or is a fused heterocyclic or fused heteroaryl ring, providedthat when

is present, Y′ is C; and

R¹⁶ and R¹⁷ are each independently H, halo, cyano, (C₁-C₆)alkoxycarbonyl, aminomethyl, t-butyl, H₂NSO₂—, Me₂NSO₂—, (C₁-C₆)alkoxy,MeSO₂—, MeSO—, MeS—, NR⁸R⁹, or hydroxy

What is also provided is a compound of Formula VI

or a pharmaceutically acceptable salt thereof wherein

is a bond or is absent;

Z is C—H, C-halo, C—(C₁-C₆)alkyl, C-halo(C₁-C₆)alkyl, C—(C₁-C₆)alkoxy,or N;

G is H, halo, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,

—CH₂O—(C₁-C₆)alkyl, —CH₂—CO₂(C₁-C₆)alkyl, —CH₂—CONH₂, or—CH₂—CONH(C₁-C₆)alkyl;

Q is NH or is absent;

X^(II) is CH₂, CH, NH or N;

R¹⁰ and R¹¹ are each independently H, —OH, halo, alkyl, haloalkyl,—NR⁸R⁹, —OR², —CN, —CH₂OH, —CH₂—NR³R⁴, aryl, monocyclic heteroaryl,alkylaryl, —CH═O, —CH₂OR², —COR², —CO₂R², or —CONR³R⁴ or are takentogether to form ═O, ═NOR², ═C(C₁-C₆alkyl)₂, or ═CR²H, with the provisothat when “ - - - ” is a bond, R¹¹ is absent, and X^(II) is CH or N, andR¹⁰ is H, —OH, halo, alkyl, haloalkyl, —NR⁸R⁹, —OR², —CN, —CH₂OH,—CH₂—NR³R⁴, aryl, monocyclic heteroaryl, alkylaryl, —CH═O, —CH₂OR²,—COR², —CO₂R², or —CONR³R⁴;

R¹ is OH, —O—(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, (C₃-C₇)heterocycloalkyl,(C₄-C₇)cycloalkenyl, (C₄-C₇)heterocycloalkenyl, aryl, monocyclicheteroaryl, or —NR³R⁴, wherein R³ and R⁴ are independently H,(C₁-C₆)alkyl, aralkyl, aryl, monocyclic heteroaryl, alkoxycarbonyl,aralkoxycarbonyl, —SO₂alkyl, or joined together to form a saturated orunsaturated 5 to 7 membered ring;

R² is H or (C₁-C₆)alkyl; and

R³ and R⁴ are independently H, (C₁-C₆)alkyl, aralkyl, aryl, monocyclicheteroaryl, alkoxycarbonyl, aralkoxycarbonyl, —SO₂alkyl, or joinedtogether to form a 5 to 7 membered ring;

R¹² and R¹³ are each independently H, halo, (C₁-C₆)alkyl, orhalo(C₁-C₆)alkyl, or (C₁-C₆)alkoxy;

R¹⁴ and R¹⁵ are each independently H, halo, alkyl, or haloalkyl, orNR⁸R⁹ wherein R⁸ and R⁹ are as defined for R³ and R⁴;

X and Y are each independently C or N, provided that when one of X or Yis N, R¹⁴ or

R¹⁵ is absent at that position.

What is also provided is a compound of Formula VII

or a pharmaceutically acceptable salt thereof wherein

G is H, halo, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,

—CH₂O—(C₁-C₆)alkyl, —CH₂—CO₂(C₁-C₆)alkyl, —CH₂—CONH₂, or—CH₂—CONH(C₁-C₆)alkyl;

X^(II) is CH₂, CH, NH or N;

R¹⁰ and R¹¹ are each independently H, —OH, halo, alkyl, haloalkyl,—NR⁸R⁹, —OR², —CN, —CH₂OH, —CH₂—NR³R⁴, aryl, monocyclic heteroaryl,alkylaryl, —CH═O, —CH₂OR², —COR², —CO₂R², or —CONR³R⁴ or are takentogether to form ═O, ═NOR², ═C(C₁-C₆alkyl)₂, or ═CR²H, with the provisothat when

is a bond, R¹¹ is absent, and X^(II) is CH or N, and R¹⁰ is H, —OH,halo, alkyl, haloalkyl, —NR⁸R⁹, —OR², —CN, —CH₂OH, —CH₂—NR³R⁴, aryl,monocyclic heteroaryl, alkylaryl, —CH═O, —CH₂OR², —COR², —CO₂R², or—CONR³R⁴;

R¹² and R¹³ are each independently H, halo, (C₁-C₆)alkyl, orhalo(C₁-C₆)alkyl, or (C₁-C₆)alkoxy;

R¹⁴ and R¹⁵ are each independently H, halo, alkyl, or haloalkyl, orNR⁸R⁹ wherein R⁸ and R⁹ are as defined for R³ and R⁴;

X and Y are each independently C or N, provided that when one of X or Yis N, R¹⁴ or

R¹⁵ is absent at that position; and

is an optionally substituted 4, 5, 6 or 7-membered ring;

wherein R^(x) and R^(y) are H, halo, hydroxymethyl, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, or wherein R^(x) and R^(y) are H, halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)carboxyalkyl, or taken together are O═;

X^(III) is CH₂, O, S, NH, or N(C₁-C₆)alkyl, provided that when R^(x) andR^(y) taken together are O═, X^(III) is CH₂.

What is also provided is a compound of Formula VIII

or a pharmaceutically acceptable salt or tautomer thereof wherein

is a bond or is absent;

Z is C—H, C-halo, C—(C₁-C₆)alkyl, C-halo(C₁-C₆)alkyl, C—(C₁-C₆)alkoxy,or N;

G is H, halo, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,

—CH₂O—(C₁-C₆)alkyl, —CH₂—CO₂(C₁-C₆)alkyl, —CH₂—CONH₂, or—CH₂—CONH(C₁-C₆)alkyl;

X^(II) is CH₂, CH, NH or N;

R¹⁰ and R¹¹ are each independently H, —OH, halo, alkyl, haloalkyl,—NR⁸R⁹, —OR², —CN, —CH₂OH, —CH₂—NR³R⁴, aryl, monocyclic heteroaryl,alkylaryl, —CH═O, —CH₂OR², —COR², —CO₂R², or —CONR³R⁴ or are takentogether to form ═O, ═NOR², ═C(C₁-C₆alkyl)₂, or ═CR²H, with the provisothat when

is a bond, R¹¹ is absent, and X^(II) is CH or N, and R¹⁰ is H, —OH,halo, alkyl, haloalkyl, —NR⁸R⁹, —OR², —CN, —CH₂OH, —CH₂—NR³R⁴, aryl,monocyclic heteroaryl, alkylaryl, —CH═O, —CH₂OR², —COR², —CO₂R², or—CONR³R⁴;

R¹² and R¹³ are each independently H, halo, (C₁-C₆)alkyl, orhalo(C₁-C₆)alkyl, or (C₁-C₆)alkoxy;

R¹⁴ and R¹⁵ are each independently H, halo, alkyl, or haloalkyl, orNR⁸R⁹ wherein R⁸ and R⁹ are as defined for R³ and R⁴;

X and Y are each independently C or N, provided that when one of X or Yis N, R¹⁴ or

R¹⁵ is absent at that position; and

Y^(II) is CH₂, CH(C₁-C₆alkyl), or N; and

R¹⁸ is H, (C₁-C₆)alkyl, hydroxymethyl, CH₂O—(C₁-C₆)alkyl, or NR³R⁴.

What is also provided is a compound of Formula IX

or a pharmaceutically acceptable salt thereof wherein

is a bond or is absent;

Z is C—H, C-halo, C—(C₁-C₆)alkyl, C-halo(C₁-C₆)alkyl, C—(C₁-C₆)alkoxy,or N;

G is H, halo, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,—CH₂O—(C₁-C₆)alkyl, —CH₂—CO₂(C₁-C₆)alkyl, —CH₂—CONH₂, or—CH₂—CONH(C₁-C₆)alkyl;

X^(II) is CH₂, CH, NH or N;

R¹⁰ and R¹¹ are each independently H, —OH, halo, alkyl, haloalkyl,—NR⁸R⁹, —OR², —CN, —CH₂OH, —CH₂—NR³R⁴, aryl, monocyclic heteroaryl,alkylaryl, —CH═O, —CH₂OR², —COR², —CO₂R², or —CONR³R⁴ or are takentogether to form ═O, ═NOR², ═C(C₁-C₆alkyl)₂, or ═CR²H, with the provisothat when

is a bond, R¹¹ is absent, and X^(II) is CH or N, and R¹⁰ is H, —OH,halo, alkyl, haloalkyl, —NR⁸R⁹, —OR², —CN, —CH₂OH, —CH₂—NR³R⁴, aryl,monocyclic heteroaryl, alkylaryl, —CH═O, —CH₂OR², —COR², —CO₂R², or—CONR³R⁴;

R¹² and R¹³ are each independently H, halo, (C₁-C₆)alkyl, orhalo(C₁-C₆)alkyl, or (C₁-C₆)alkoxy;

R¹⁴ and R¹⁵ are each independently H, halo, alkyl, or haloalkyl, orNR⁸R⁹ wherein R⁸ and R⁹ are as defined for R³ and R⁴;

X and Y are each independently C or N, provided that when one of X or Yis N, R¹⁴ or R¹⁵ is absent at that position;

X^(a), Y^(a), and Z^(a) are each independently CH, CR¹⁸ or N; and

R¹⁸ is H, (C₁-C₆)alkyl, hydroxymethyl, CH₂O—(C₁-C₆)alkyl, or NR³R⁴.

The invention also provides a compound of Formula X

or a pharmaceutically acceptable salt thereof wherein

is a bond or is absent;

Z is C—H, C-halo, C—(C₁-C₆)alkyl, C-halo(C₁-C₆)alkyl, C—(C₁-C₆)alkoxy,or N;

G is H, halo, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl,—CH₂O—(C₁-C₆)alkyl, —CH₂—CO₂(C₁-C₆)alkyl, —CH₂—CONH₂, or—CH₂—CONH(C₁-C₆)alkyl;

X^(II) is CH₂, CH, NH or N;

R¹⁰ and R¹¹ are each independently H, —OH, halo, alkyl, haloalkyl,—NR⁸R⁹, —OR², —CN, —CH₂OH, —CH₂—NR³R⁴, aryl, monocyclic heteroaryl,alkylaryl, —CH═O, —CH₂OR², —COR², —CO₂R², or —CONR³R⁴ or are takentogether to form ═O, ═NOR², ═C(C₁-C₆alkyl)₂, or ═CR²H, with the provisothat when “ - - - ” is a bond, R¹¹ is absent, and X^(II) is CH or N, andR¹⁰ is H, —OH, halo, alkyl, haloalkyl, —NR⁸R⁹, —OR², —CN, —CH₂OH,—CH₂—NR³R⁴, aryl, monocyclic heteroaryl, alkylaryl, —CH═O, —CH₂OR²,—COR², —CO₂R², or —CONR³R⁴;

R¹² and R¹³ are each independently H, halo, (C₁-C₆)alkyl, orhalo(C₁-C₆)alkyl, or (C₁-C₆)alkoxy;

R¹⁴ and R¹⁵ are each independently H, halo, alkyl, or haloalkyl, orNR⁸R⁹ wherein R⁸ and R⁹ are as defined for R³ and R⁴;

X and Y are each independently C or N, provided that when one of X or Yis N, R¹⁴ or R¹⁵ is absent at that position;

J₁, J₂, J₃, and J₄ are C or one of J₁, J₂, J₃, and J₄ is N;

R¹⁹, R²⁰, R²¹, and R²² are each independently H, halo, hydroxy, NH₂,NR²³R²⁴, NO₂, SH, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, (C₁-C₆)alkanoyl,(C₁-C₆)alkoxycarbonyl, or (C₁-C₆)alkoxy, wherein R²³ and R²⁴ are eachindependently H, (C₁-C₆)alkyl, aralkyl, aryl, monocyclic heteroaryl,alkoxycarbonyl, aralkoxycarbonyl, —SO₂alkyl, or joined together to forma saturated or unsaturated 3 to 7 membered ring, or R¹⁹ and R²⁰, R²⁰ andR²¹, or R²¹ and R²², together with the carbons to which they areattached, form a 5, 6, or 7 membered saturated or unsaturated cycloalkylor heterocycloalkyl ring, or an aryl or heteroaryl ring;

provided that when any of J₁, J₂, J₃, or J₄ is N, R¹⁹, R²⁰, R²¹, or R²²is absent at that position.

The invention is also directed to a compound which is:

Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(2,4-difluoro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]1-p-tolylamide;

Pyrrolidine-1,2-dicarboxylic acid2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]1-[(4-methoxy-phenyl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(4-bromo-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]1-[(4-isopropyl-phenyl)-amide];

Pyrrolidine-1,2-dicarboxylic acid2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]1-phenylamide;

Pyrrolidine-1,2-dicarboxylic acid2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]1-[(4-trifluoromethyl-phenyl)-amide];

Pyrrolidine-1,2-dicarboxylic acid2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]1-[(3-methoxy-phenyl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(4-ethyl-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(3,4-difluoro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(3-fluoro-4-methyl-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[5-(2-sulfamoyl-phenyl)-pyridin-2-yl]-amide};

Pyrrolidine-1,2-dicarboxylic acid2-[(3-chloro-2′-methanesulfonyl-biphenyl-4-yl)-amide]1-[(5-chloro-pyridin-2-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid2-[(3-chloro-2′-methanesulfonyl-biphenyl-4-yl)-amide]1-[(4-chloro-phenyl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[5-(2-sulfamoyl-phenyl)-pyridin-2-yl]-amide};

Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(1H-tetrazol-5-yl)-phenyl]-amide};

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4-Oxo-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4-Methylene-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4-Methyl-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4-Amino-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4-Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

1-(4-Chloro-phenylcarbamoyl)-5-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-3-carboxylicacid;

1-(4-Chloro-phenylcarbamoyl)-5-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-3-carboxylicacid methyl ester;

Pyrrolidine-1,2,4-tricarboxylic acid 4-amide1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4-Aminomethyl-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4-Methoxymethyl-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4-Methylamino-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4-Acetylamino-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4-Methanesulfonylamino-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

5-Oxo-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

Piperidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

Morpholine-3,4-dicarboxylic acid4-[(4-chloro-phenyl)-amide]3-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

Piperazine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

2,5-Dihydro-pyrrole-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfonyl-3-methyl-biphenyl-4-yl)-amide];

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfonyl-3-methyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfonyl-biphenyl-4-yl)-amide];

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfonyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[5-(2-methanesulfonyl-phenyl)-pyrimidin-2-yl]-amide};

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[5-(2-methanesulfonyl-phenyl)-pyrimidin-2-yl]-amide};

Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[5-(2-methanesulfonyl-phenyl)-3-methyl-pyridin-2-yl]-amide};

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[5-(2-methanesulfonyl-phenyl)-3-methyl-pyridin-2-yl]-amide};

Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfonyl-3-trifluoromethyl-biphenyl-4-yl)-amide];

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfonyl-3-trifluoromethyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[5-(2-methanesulfonyl-phenyl)-6-methyl-pyridin-2-yl]-amide};

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[5-(2-methanesulfonyl-phenyl)-6-methyl-pyridin-2-yl]-amide};

Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-ethyl-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-ethyl-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3,5-difluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3,5-dichloro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3,5-dichloro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfonyl-3,5-dimethyl-biphenyl-4-yl)-amide];

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfonyl-3,5-dimethyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid2-[(3-chloro-2′-methanesulfonyl-5-methyl-biphenyl-4-yl)-amide]1-[(4-chloro-phenyl)-amide];

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid2-[(3-chloro-2′-methanesulfonyl-5-methyl-biphenyl-4-yl)-amide]1-[(4-chloro-phenyl)-amide];

Pyrrolidine-1,2-dicarboxylic acid2-[(2-chloro-2′-methanesulfonyl-biphenyl-4-yl)-amide]1-[(4-chloro-phenyl)-amide];

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid2-[(2-chloro-2′-methanesulfonyl-biphenyl-4-yl)-amide]1-[(4-chloro-phenyl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfonyl-2-methyl-biphenyl-4-yl)-amide];

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfonyl-2-methyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4-{[1-(4-Chloro-phenylcarbamoyl)-pyrrolidine-2-carbonyl]-amino}-2′-methanesulfonyl-biphenyl-3-carboxylicacid methyl ester;

4-{[1-(4-Chloro-phenylcarbamoyl)-4-hydroxy-pyrrolidine-2-carbonyl]-amino}-2′-methanesulfonyl-biphenyl-3-carboxylicacid methyl ester;

Pyrrolidine-1,2-dicarboxylic acid2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]1-[(4-trifluoromethyl-phenyl)-amide];

Pyrrolidine-1,2-dicarboxylic acid2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]1-m-tolylamide;

Pyrrolidine-1,2-dicarboxylic acid1-[(3-acetyl-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-2-methyl-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(2-fluoro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(3-chloro-4-fluoro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(3-chloro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(4-cyano-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-2-methyl-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(3,4-dichloro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]1-[(3-trifluoromethyl-phenyl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(4-dimethylamino-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

(2S)-Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-cyano-phenyl)-amide];

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]1-[(4-fluoro-phenyl)-amide];

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]1-p-tolylamide;

4-Oxo-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];and

4-Fluoro-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];or

a pharmaceutically acceptable salt thereof.

A compound which is:

(R)-Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

(S)-Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

(2R,4S)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]1-[(4-fluoro-phenyl)-amide];

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]1-p-tolylamide;

(2R)-4-Oxo-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];and

(2R,4S)-4-Fluoro-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];or a

pharmaceutically acceptable salt thereof.

The invention is also directed to a compound which is:

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide);

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Propoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Propoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Fluoro-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-azetidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-azetidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-azepan-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-azepan-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-hydroxymethyl-5-oxo-pyrrolidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2,3-dimethyl-5-oxo-2,5-dihydro-pyrazol-1-yl)-phenyl]-amide};

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2-hydroxymethyl-pyrrolidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-pyrrolidin-1-yl-phenyl)-amide];

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-pyrazol-1-yl-phenyl)-amide];

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-fluoro-4-pyrazol-1-yl-phenyl)-amide];

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-[1,2,4]triazol-1-yl-phenyl)-amide];

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-[1,2,3]triazol-2-yl-phenyl)-amide];

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-[1,2,3]triazol-1-yl-phenyl)-amide];

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid2-[(4-acetylamino-phenyl)-amide]1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(cyclopentanecarbonyl-amino)-phenyl]-amide};and

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-pyrimidin-5-yl-phenyl)-amide]; or

a pharmaceutically acceptable salt thereof.

A compound which is:

1-(4-Chloro-phenylcarbamoyl)-5-[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenylcarbamoyl]-pyrrolidine-3-carboxylicacid;

1-(4-Chloro-phenylcarbamoyl)-5-[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenylcarbamoyl]-pyrrolidine-3-carboxylicacid methyl ester;

1-(4-Chloro-phenylcarbamoyl)-5-[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenylcarbamoyl]-pyrrolidine-3-carboxylicacid ethyl ester;

Pyrrolidine-1,2,4-tricarboxylic acid 4-amide1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

4-Cyano-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

4-(1H-Tetrazol-5-yl)-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

4-Aminomethyl-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

4-Methylaminomethyl-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

4-Dimethylaminomethyl-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

4-Acetyl-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

Pyrrolidine-1,2,4-tricarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}4-methylamide;

Pyrrolidine-1,2,4-tricarboxylic acid1-[(4-chloro-phenyl)-amide]4-dimethylamide2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

4-Trifluoromethyl-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

4-Methyl-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

4-Isopropoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

4-Fluoro-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-phenyl)-pyrrolidine-2-carboxylicacid;

1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-hydroxy-pyrrolidine-2-carbonyl]-amino}-phenyl)-pyrrolidine-2-carboxylicacid;

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl)-amide];

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amide];

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[5-(2-oxo-piperidin-1-yl)-pyrimidin-2-yl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-(2-oxo-piperidin-1-yl)-pyrimidin-5-yl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[5-(2-oxo-piperidin-1-yl)-pyrimidin-2-yl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-(2-oxo-piperidin-1-yl)-pyrimidin-5-yl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}1-[(5-fluoro-pyridin-2-yl)-amide];

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-fluoro-pyridin-2-yl)-amide]2-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl)-amide];

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-fluoro-pyridin-2-yl)-amide]2-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amide];

4-Fluoro-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl)-amide];

4-Fluoro-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl)-amide];

4-Fluoro-pyrrolidine-1,2-dicarboxylic acid1-[(5-fluoro-pyridin-2-yl)-amide]2-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl)-amide];

4-Fluoro-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amide];

4-Fluoro-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amide];

4-Fluoro-pyrrolidine-1,2-dicarboxylic acid1-[(5-fluoro-pyridin-2-yl)-amide]2-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amide];

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-hydroxymethyl-5-oxo-pyrrolidin-1-yl)-phenyl]-amide};

1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-5-oxo-pyrrolidine-2-carboxylicacid;

1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-5-oxo-pyrrolidine-2-carboxylicacid;

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(4,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)-2-fluoro-phenyl]-amide};

[1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-2,5-dioxo-imidazolidin-4-yl]-aceticacid;

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(5,5-dimethyl-2,4-dioxo-oxazolidin-3-yl)-2-fluoro-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2,5-dioxo-pyrrolidin-1-yl)-2-fluoro-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-oxazolidin-3-yl)-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2,5-dioxo-oxazolidin-3-yl)-2-fluoro-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-imidazolidin-1-yl)-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2,5-dioxo-imidazolidin-1-yl)-2-fluoro-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-phenyl]-amide};

3-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-2-oxo-imidazolidine-4-carboxylicacid;

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2,4,5-trioxo-imidazolidin-1-yl)-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-2-fluoro-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(2-aminomethyl-5-oxo-pyrrolidin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(2-aminomethyl-5-oxo-pyrrolidin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(2-carbamoyl-5-oxo-pyrrolidin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(2-carbamoyl-5-oxo-pyrrolidin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(2,2-bis-hydroxymethyl-5-oxo-pyrrolidin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

3-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-2-oxo-imidazolidine-4-carboxylicacid;

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3,3-dimethyl-2,5-dioxo-pyrrolidin-1-yl)-2-fluoro-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3,3,4-trimethyl-2,5-dioxo-pyrrolidin-1-yl)-phenyl]-amide};

1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-5-oxo-pyrrolidine-2,2-dicarboxylicacid;

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-methyl-5-oxo-pyrrolidin-1-yl)-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-methyl-6-oxo-piperidin-1-yl)-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-hydroxy-2-oxo-piperidin-1-yl)-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(5-methyl-2,6-dioxo-tetrahydro-pyrimidin-1-yl)-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-tetrahydro-pyrimidin-1-yl)-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2,5-dioxo-piperazin-1-yl)-2-fluoro-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-hydroxy-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-methoxy-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(6-methyl-2-oxo-4-trifluoromethyl-2H-pyridin-1-yl)-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2,6-dioxo-piperidin-1-yl)-2-fluoro-phenyl]-amide};

1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-2-oxo-piperidine-3-carboxylicacid;

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(5,5-dihydroxy-2,4,6-trioxo-tetrahydro-pyrimidin-1-yl)-2-fluoro-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2,4,6-trioxo-tetrahydro-pyrimidin-1-yl)-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)-2-fluoro-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-hydroxy-4-oxo-azetidin-1-yl)-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(acetyl-methyl-amino)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

4-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-1H-pyrrole-3-carboxylicacid;

2-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-2H-pyrazole-3-carboxylicacid;

1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-1H-imidazole-2-carboxylicacid;

1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-1H-pyrrole-2-carboxylicacid;

3-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-1H-pyrrole-2-carboxylicacid;

3-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-furan-2-carboxylicacid;

3-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-thiophene-2-carboxylicacid;

4-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-furan-3-carboxylicacid;

4-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-thiophene-3-carboxylicacid;

4,5-Dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

3-Oxo-pyrazolidine-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

3-Oxo-pyrazolidine-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

4,5-Dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-{[4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

4,5-Dihydro-pyrazole-1,5-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]5-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

4,5-Dihydro-pyrazole-1,5-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]5-{[4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

4,5-Dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl)-amide];

4,5-Dihydro-pyrazole-1,5-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]5-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl)-amide];

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(3,5′-difluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(5′-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(3,5′-difluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3,5′-difluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(5′-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3,5′-difluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(3,5′-difluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3,5′-difluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3,5′-difluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide],or

a pharmaceutically acceptable salt thereof.

The invention is also directed to a compound which is:

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-pyrazol-1-yl-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-fluoro-4-pyrazol-1-yl-phenyl)-amide];

(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-fluoro-4-pyrazol-1-yl-phenyl)-amide];

(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-pyrazol-1-yl-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-methyl-pyrazol-1-yl)-phenyl]-amide};

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(5-methyl-pyrazol-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(5-methyl-pyrazol-1-yl)-phenyl]-amide};

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3,5-dimethyl-pyrazol-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3,5-dimethyl-pyrazol-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3,5-dimethyl-pyrazol-1-yl)-2-fluoro-phenyl]-amide};

(2R,4S)-4-Amino-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

(2R,4R)-4-Amino-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

(2R)-4-Hydroxyimino-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methylsulfamoyl-biphenyl-4-yl)-amide];

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-dimethylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

(2R,4S)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

(2R,4R)-4-Fluoro-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

(2R)-4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]1-[(4-fluoro-phenyl)-amide];

(2R,4R)-4-Acetylamino-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

(2R,4R)-4-Methanesulfonylamino-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

(2R,4S)-4-(1H-Tetrazol-5-yl)-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

(2R,4S)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Cyano-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

(2R,4R)-4-(1H-Tetrazol-5-yl)-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Trifluoromethyl-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-cyano-3-fluoro-biphenyl-4-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-[(2′-aminomethyl-3-fluoro-biphenyl-4-yl)-amide]1-[(4-chloro-phenyl)-amide];

(2R,4R)-4′-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3′-fluoro-biphenyl-2-carboxylicacid methyl ester;

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2,5-dihydro-pyrrole-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-dimethylcarbamoyl-2-fluoro-phenyl)-amide];

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(pyrrolidine-1-carbonyl)-phenyl]-amide};

Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(pyrrolidine-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2-methyl-pyrrolidine-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(ethyl-methyl-carbamoyl)-phenyl]-amide};

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-dimethylcarbamoyl-phenyl)-amide];

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2R-methyl-pyrrolidine-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2S-methyl-pyrrolidine-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(pyrrolidine-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(pyrrolidine-1-carbonyl)-2-pyrrolidin-1-yl-phenyl]-amide};

(2R,4R)-4-{[1-(4-Chloro-phenylcarbamoyl)-4-hydroxy-pyrrolidine-2-carbonyl]-amino}-3-pyrrolidin-1-yl-benzoicacid methyl ester;

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(azetidine-1-carbonyl)-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(pyrrolidine-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(pyrrolidine-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(4-dimethylcarbamoyl-phenyl)-amide];

(2R,4R)-4-{[1-(4-Chloro-phenylcarbamoyl)-4-hydroxy-pyrrolidine-2-carbonyl]-amino}-3-dimethylamino-benzoicacid methyl ester;

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(pyrrolidine-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-dimethylcarbamoyl-phenyl)-amide];

(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(pyrrolidine-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-dimethylcarbamoyl-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(pyrrolidine-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(pyrrolidine-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-dimethylcarbamoyl-2-fluoro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-methyl-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-methyl-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-fluoro-4-quinolin-8-yl-phenyl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3,5-difluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfonyl-2-methyl-biphenyl-4-yl)-amide];

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfonyl-biphenyl-4-yl)-amide];

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfinyl-biphenyl-4-yl)-amide];

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-methyl-2′-methylsulfanyl-biphenyl-4-yl)-amide];

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfonyl-3-methyl-biphenyl-4-yl)-amide];

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfonyl-3-trifluoromethyl-biphenyl-4-yl)-amide];

5-Methyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

3-Hydroxymethyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

4,5-Dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

(R) 4,5-Dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

4,5-Dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

4,5-Dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide];

1-(4-Chloro-phenylcarbamoyl)-5-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-4,5-dihydro-1H-pyrazole-3-carboxylicacid ethyl ester;

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methoxy-biphenyl-4-yl)-amide];

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-hydroxy-biphenyl-4-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-fluoro-4-iodo-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-hydroxy-2-oxo-piperidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-tetrahydro-pyrimidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-imidazolidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-oxazolidin-3-yl)-phenyl]-amide};

(2R,4R)-1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-2-oxo-piperidine-3-carboxylicacid ethyl ester;

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-methoxy-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(3-methoxy-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(3-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-morpholin-4-yl-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2-methyl-5-oxo-pyrrolidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(2-methyl-5-oxo-pyrrolidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(4-methoxy-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(4-methoxy-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(5-chloro-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid2-[(4-tert-butyl-phenyl)-amide]1-[(4-chloro-phenyl)-amide];

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2[(3,5′difluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amide];

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl)-amide];

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(2,3-dimethyl-5-oxo-2,5-dihydro-pyrazol-1-yl)-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2,3-dimethyl-5-oxo-2,5-dihydro-pyrazol-1-yl)-phenyl]-amide};

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-oxo-2H-[1,3′]bipyridinyl-6′-yl)-amide];

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl)-amide]-TFASalt;

4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl)-amide];

4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-oxo-2H-[1,3′]bipyridinyl-6′-yl)-amide];or

4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(6-oxo-6H-pyridazin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(6-methyl-5-oxo-5H-[1,2,4]triazin-4-yl)-phenyl]amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-chloro-5-methyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3-methyl-5-oxo-4,5-dihydro-pyrazol-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(5-chloro-3-methyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3,5-dimethoxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(5-methoxy-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-3-pyrrol-1-yl-2H-pyridin-1-yl)-phenyl]amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-3-phenyl-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-methyl-2-oxo-pyrrolidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-methyl-2-oxo-imidazolidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3,5-dimethyl-2-oxo-imidazolidin-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3,5,5-trimethyl-2-oxo-imidazolidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-isopropyl-5,5-dimethyl-2-oxo-imidazolidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(5-methyl-2-oxo-imidazolidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(5,5-dimethyl-2-oxo-imidazolidin-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3,4-dimethyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(4-chloro-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(3-methyl-2-oxo-pyrrolidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(3-methyl-2-oxo-imidazolidin-1-yl)-phenyl]amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(3,5-dimethyl-2-oxo-imidazolidin-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(3,5,5-trimethyl-2-oxo-imidazolidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(3-isopropyl-5,5-dimethyl-2-oxo-imidazolidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(5-methyl-2-oxo-imidazolidin-1-yl)-phenyl]amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(5,5-dimethyl-2-oxo-imidazolidin-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(3,4-dimethyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(4-chloro-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

or a pharmaceutically acceptable salt thereof.

The invention is also directed to a compound which is:

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-quinolin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-oxo-3H-isoquinolin-2-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(1-oxo-1H-isoquinolin-2-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(5-oxo-5H-[1,2,4]triazin-4-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(6-oxo-6H-pyrimidin-1-yl)-phenyl]-amide};

2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyrazin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyrimidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-[1,3,5]triazin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(6-methyl-2-oxo-2H-[1,3′]bipyridinyl-6′-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(1-methyl-iH-imidazol-2-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(1-methyl-iH-pyrrol-2-yl)-phenyl]-amide};

(2R,4R)-5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid5-[(4-chloro-phenyl)-amide]6-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridine-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-methyl-3H-imidazol-4-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-methyl-2H-pyrazol-3-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[5-(2,5-dihydro-pyrrole-1-carbonyl)-pyridin-2-yl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-methyl-5-oxo-2,5-dihydro-pyrazol-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(5-methoxymethyl-3-methyl-pyrazol-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-methoxymethyl-5-methyl-pyrazol-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(5-ethyl-3-methyl-pyrazol-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(5-isobutyl-3-methyl-pyrazol-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(5-isopropyl-pyrazol-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(5-ethyl-pyrazol-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(5-isobutyl-pyrazol-1-yl)-phenyl]-amide};

(2R,4R)-2-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolodine-2-carbonyl]-amino}-3-fluoro-phenyl)-2H-pyrazole-3-carboxylicacid methyl ester;

(2R,4R)-2-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolodine-2-carbonyl]-amino}-3-fluoro-phenyl)-2H-pyrazole-3-carboxylicacid;

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(5-methoxymethyl-pyrazol-1-yl)-phenyl]-amide};

(2R,4R)-5-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-oxazole-4-carboxylicacid ethyl ester;

(2R,4R)-5-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-hydroxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-oxazole-4-carboxylicacid ethyl ester;

(2R,4R)-5-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-oxazole-4-carboxylicacid;

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(4-methoxymethyl-oxazol-5-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(4-ethyl-oxazol-5-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(4-isopropyl-oxazol-5-yl)-phenyl]-amide};

(2R,4R)-5-(6-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-pyridin-3-yl)-oxazole-4-carboxylicacid ethyl ester;

(2R,4R)-5-(6-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-pyridin-3-yl)-oxazole-4-carboxylicacid;

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[5-(4-methoxymethyl-oxazol-5-yl)-pyridin-2-yl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[5-(4-ethyl-oxazol-5-yl)-pyridin-2-yl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[5-(4-vinyl-oxazol-5-yl)-pyridin-2-yl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[5-(4-isobutyl-oxazol-5-yl)-pyridin-2-yl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(4-methyl-isoxazol-3-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(4-methyl-isoxazol-3-yl)-phenyl]-amide};

(2R,4R)-3-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-isoxazole-4-carboxylicacid methyl ester;

(2R,4R)-3-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-isoxazole-4-carboxylicacid;

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(4-methoxymethyl-isoxazol-3-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(4-isopropyl-isoxazol-3-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(4-cyclopropyl-isoxazol-3-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(4-cyclopropyl-isoxazol-3-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-methyl-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-methyl-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-methyl-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-[(4-chloro-phenyl)-amide]1-{[2,6-difluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-[(5-chloro-pyridin-2-yl)-amide]1-{[2,6-difluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid2-[(4-chloro-phenyl)-amide]1-{[2,6-difluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid2-[(5-chloro-pyridin-2-yl)-amide]1-{[2,6-difluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(5′-methyl-2-oxo-2H-[1,3′]bipyridinyl-6′-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(5′-methyl-2-oxo-2H-[1,3′]bipyridinyl-6′-yl)-amide];

(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(5′-methyl-2-oxo-2H-[1,3′]bipyridinyl-6′-yl)-amide];

(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(5′-methyl-2-oxo-2H-[1,3′]bipyridinyl-6′-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methyl-2-oxo-2H-[1,3′]bipyridinyl-6′-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(2′-methyl-2-oxo-2H-[1,3′]bipyridinyl-6′-yl)-amide];

(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methyl-2-oxo-2H-[1,3′]bipyridinyl-6′-yl)-amide];

(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(2′-methyl-2-oxo-2H-[1,3′]bipyridinyl-6′-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(ethyl-isopropyl-carbamoyl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(ethyl-isopropyl-carbamoyl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3-ethyl-pyrrolidine-l1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3-ethyl-pyrrolidine-l1-carbonyl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3R-amino-pyrrolidine-1-carbonyl)-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3R-amino-pyrrolidine-1-carbonyl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3S-amino-pyrrolidine-1-carbonyl)-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3S-amino-pyrrolidine-1-carbonyl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3R-methylamino-pyrrolidine-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3R-methylamino-pyrrolidine-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3S-methylamino-pyrrolidine-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3S-methylamino-pyrrolidine-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3R-ethylamino-pyrrolidine-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3R-ethylamino-pyrrolidine-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3S-ethylamino-pyrrolidine-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3S-ethylamino-pyrrolidine-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(2,5-dihydro-pyrrole-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2,5-dihydro-pyrrole-1-carbonyl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(2,5-dihydro-pyrrole-1-carbonyl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(pyrrole-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(pyrrole-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(pyrrole-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(pyrrole-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(5-fluoro-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid;

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(6-hydroxy-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylicacid;

(2R,4R)-1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-6-oxo-1,6-dihydro-pyridine-2-carboxylicacid methyl ester;

(2R,4R)-[1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-phenyl)-2,5-dioxo-imidazolidin-4-yl]-aceticacid;

(2R,4R)-1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylicacid methyl ester;

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-3-trifluoromethyl-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(4-hydroxy-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-6-oxo-1,6-dihydro-pyridine-2-carboxylicacid;

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-5-trifluoromethyl-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(6-cyclopropyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid ethyl ester;

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3,3-dimethyl-2-oxo-azetidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(7-oxo-7H-thieno[2,3-c]pyridin-6-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-1-aza-spiro[4.5]dec-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-benzoyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-acetylsulfamoyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-thiazolidin-3-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-methyl-2-oxo-piperidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-3-sulfamoyl-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-amino-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-3-phenoxy-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2,2-dimethyl-5-oxo-pyrrolidin-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-nitro-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylicacid tert-butyl ester;

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2,5-dioxo-pyrrolidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-benzothiazol-2-yl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-amino-4,6-dimethyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3-diethylaminomethyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-aminomethyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-methyl-5-nitro-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-Acetic acid1-(4-{[1-(4-chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridin-3-ylester;

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-({4-[3-(cyclopentanecarbonyl-amino)-2-oxo-2H-pyridin-1-yl]-2-fluoro-phenyl}-amide);

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(5-amino-3-methyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-({2-fluoro-4-[2-oxo-3-(pyridin-4-ylcarbamoyl)-2H-pyridin-1-yl]-phenyl}-amide);

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3,5-dichloro-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-amino-5-bromo-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3-cyano-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3-cyano-2-oxo-5-phenyl-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3-ethyl-6-methyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3-cyano-4-dimethylamino-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(4-methyl-3-nitro-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(5-nitro-2-oxo-3-trifluoromethyl-2H-pyridin-1-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(5-amino-6-oxo-6H-[3,4′]bipyridinyl-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(5-chloro-3-nitro-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-carbamoyl-2-oxo-5-trifluoromethyl-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-5-Bromo-1-(4-{[1-(4-chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylicacid isobutyl ester;

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-chloro-2-oxo-5-trifluoromethyl-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-bromo-5-chloro-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(5-bromo-3-nitro-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-nitro-2-oxo-5-trifluoromethyl-2H-pyridin-1-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(5-methyl-3-nitro-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-5-Chloro-1-(4-{[1-(4-chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylicacid methyl ester;

(2R,4R)-5-Chloro-1-(4-{[1-(4-chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylicacid;

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(4-benzyloxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(4-amino-5-fluoro-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(6-methyl-3-oxo-3H-isoquinolin-2-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(4-methyl-5-nitro-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(5-acetylamino-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(4-amino-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(6-oxo-6H-[3,4′]bipyridinyl-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(4-bromo-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(1-oxo-1H-[2,6]naphthyridin-2-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(5-bromo-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(4-oxo-1,4-dihydro-imidazo[4,5-c]pyridin-5-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(5-chloro-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(5-fluoro-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-1-(4-{[1-(5-Chloro-pyridin-2-ylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid;

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(6-hydroxy-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-1-(4-{[1-(5-Chloro-pyridin-2-ylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylicacid;

(2R,4R)-1-(4-{[1-(5-Chloro-pyridin-2-ylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-6-oxo-1,6-dihydro-pyridine-2-carboxylicacid methyl ester;

(2R,4R)-[1-(4-{[1-(5-Chloro-pyridin-2-ylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-phenyl)-2,5-dioxo-imidazolidin-4-yl]-aceticacid;

(2R,4R)-1-(4-{[1-(5-Chloro-pyridin-2-ylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylicacid methyl ester;

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-3-trifluoromethyl-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(4-hydroxy-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-1-(4-{[1-(5-Chloro-pyridin-2-ylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-6-oxo-1,6-dihydro-pyridine-2-carboxylicacid;

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-5-trifluoromethyl-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(6-cyclopropyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-1-(4-{[1-(5-Chloro-pyridin-2-ylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylicacid ethyl ester;

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(3-hydroxy-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(3,3-dimethyl-2-oxo-azetidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(7-oxo-7H-thieno[2,3-c]pyridin-6-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-1-aza-spiro[4.5]dec-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-benzoyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-methyl-5-oxo-pyrrolidin-1-yl)-phenyl]amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-methyl-6-oxo-piperidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-acetylsulfamoyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-thiazolidin-3-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(3-methyl-2-oxo-piperidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-3-sulfamoyl-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-amino-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-3-phenoxy-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(2,2-dimethyl-5-oxo-pyrrolidin-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(3-nitro-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-1-(4-{[1-(5-Chloro-pyridin-2-ylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylicacid tert-butyl ester;

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(2,5-dioxo-pyrrolidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-benzothiazol-2-yl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-amino-4,6-dimethyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(3-diethylaminomethyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-aminomethyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(3-methyl-5-nitro-2-oxo-2H-pyridin-1yl)-phenyl]-amide};

(2R,4R)-Acetic acid1-(4-{[-(5-chloro-pyridin-2-ylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridin-3-ylester;

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-({4-[3-(cyclopentanecarbonyl-amino)-2-oxo-2H-pyridin-1-yl]-2-fluoro-phenyl}-amide);

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(5-amino-3-methyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-({2-fluoro-4-[2-oxo-3-(pyridin-4-ylcarbamoyl)-2H-pyridin-1-yl]-phenyl}-amide);

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(3,5-dichloro-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-amino-5-bromo-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(3-cyano-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(3-cyano-2-oxo-5-phenyl-2H-pyridin-1-yl)-2-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(3-ethyl-6-methyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(3-cyano-4-dimethylamino-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(4-methyl-3-nitro-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(5-nitro-2-oxo-3-trifluoromethyl-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(5-amino-6-oxo-6H-[3,4′]bipyridinyl-1-yl)-2-fluoro-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(5-chloro-3-nitro-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-carbamoyl-2-oxo-5-trifluoromethyl-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

(2R,4R)-5-Bromo-1-(4-{[I-(5-chloro-pyridin-2-ylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylicacid isobutyl ester;

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-chloro-2-oxo-5-trifluoromethyl-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-bromo-5-chloro-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(5-bromo-3-nitro-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(3-nitro-2-oxo-5-trifluoromethyl-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(5-methyl-3-nitro-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-5-Chloro-1-(4-{[1-(5-chloro-pyridin-2-ylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylicacid methyl ester;

(2R,4R)-5-Chloro-1-(4-{[1-(5-chloro-pyridin-2-ylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylicacid;

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(4-benzyloxy-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(4-amino-5-fluoro-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(5-nitro-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(6-methyl-3-oxo-3H-isoquinolin-2-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(4-methyl-5-nitro-2-oxo-2H-pyridin-1yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(5-acetylamino-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(1-oxo-1H-isoquinolin-2-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(4-amino-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(6-oxo-6H-[3,4′]bipyridinyl-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(3-oxo-3H-isoquinolin-2-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(4-bromo-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(4-oxo-4H-furo[3,2-c]pyridin-5-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(1-oxo-1H-[2,6]naphthyridin-2-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(5-bromo-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(4-oxo-4H-thieno[3,2-c]pyridin-5-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(4-oxo-1,4-dihydro-imidazo[4,5-c]pyridin-5-yl)-phenyl]-amide};

4,5-Dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

3-Hydroxymethyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

5-Methyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

3-Methoxymethyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

4,5-Dihydro-pyrazole-1,5-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]5-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

3-Hydroxymethyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]5-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

5-Methyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]5-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

3-Methoxymethyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]5-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

4,5-Dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-{[4-(2-methyl-thiazol-4-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-2-methyl-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2-dimethylaminomethyl-imidazol-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[2-chloro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[2-chloro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

(2R,4R)-4-Methyl-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-methylamino-imidazol-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-isopropyl-imidazol-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2-ethyl-imidazol-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(2-ethyl-imidazol-1-yl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-isopropyl-imidazol-1-yl)-phenyl]-amide};

(2R,4R)-2-Ethyl-4-methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

4-Methoxy-2-methoxymethyl-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

2-Hydroxymethyl-4-methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

{1-(4-Chloro-phenylcarbamoyl)-2-[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenylcarbamoyl]-4-methoxy-pyrrolidin-2-yl}-aceticacid methyl ester;

{1-(4-Chloro-phenylcarbamoyl)-2-[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenylcarbamoyl]-4-methoxy-pyrrolidin-2-yl}-aceticacid;

4-Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

{1-(4-Chloro-phenylcarbamoyl)-5-[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenylcarbamoyl]-pyrrolidin-3-yl}-aceticacid;

{1-(4-Chloro-phenylcarbamoyl)-5-[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenylcarbamoyl]-pyrrolidin-3-yl}-aceticacid methyl ester;

(2R,4R)-4-Ethyl-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Isopropyl-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-fluoro-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(3-fluoro-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-chloro-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-chloro-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-bromo-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(3-bromo-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(5-chloro-pyridin-2-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-iodo-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(3-iodo-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(3-ethyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide};and

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3-ethyl-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide;

a pharmaceutically acceptable salt thereof.

The invention is also directed to a compound which is:

(2R,4R) 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

(2R,4R) 4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R) 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R) 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R) 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-oxo-2H-[1,3′]bipyridinyl-6′-yl)-amide];

(2R,4R) 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-methoxy-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R) 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R) 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-methyl-imidazol-1-yl)-phenyl]-amide};

(2R,4R) 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-dimethylcarbamoyl-2-fluoro-phenyl)-amide];

(2R,4R) 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(5-methyl-pyrazol-1-yl)-phenyl]-amide};

(2R,4R) 4,5-Dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

(2R,4R) 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-fluoro-4-pyrazol-1-yl-phenyl)-amide];

(2R,4R) 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(pyrrolidine-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-methyl-imidazol-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-oxo-2H-[1,3′]bipyridinyl-6′-yl)-amide];

(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-dimethylcarbamoyl-2-fluoro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(5-methyl-pyrazol-1-yl)-phenyl]-amide};

5-Methyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(4-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[2-chloro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}1-[(4-chloro-phenyl)-amide];

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-methyl-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(6-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(3-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(5-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(5-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(4-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]-amide;

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2,5-dihydrom-pyyrole-1-carbonyl)-2-fluoro-phenyl-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2,5-dihydrom-pyyrole-1-carbonyl)-phenyl-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2-methyl-5-oxo-pyrrolidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2,5-dihydro-pyrrole-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(4-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2,5-dihydro-pyrrole-1-carbonyl)-2-fluoro-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2-methyl-5-oxo-pyrrolidin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2,5-dihydro-pyrrole-1-carbonyl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(4-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]-amide};

(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2,5-dihydro-pyrrole-1-carbonyl)-2-fluoro-phenyl]-amide}

or a pharmaceutically acceptable salt thereof.

The invention is also directed to a pharmaceutical compositioncomprising a compound of formula I admixed with a carrier, diluent, orexcipient.

The invention is also directed to a method for preventing or treatingacute, subacute, and chronic thrombotic disorder in a mammal iscomprising administering to a mammal in need thereof a therapeuticallyeffective amount of a compound of any of formulas I-X.

The invention is also directed to a method of inhibiting Factor Xa in amammal, comprising administering to a mammal in need of Factor Xainhibition a Factor Xa inhibition amount of a compound of any offormulas I-X.

The invention is also directed to a process for preparing a compound ofFormula I comprising:

(a) reacting an amino acid of formula IA

with a reagent capable of placing a protecting groupP¹ on the aminogroup of an amino acid to form a protected amino acid given by formulaIB:

wherein P¹ is a protecting group and W¹ is the same as defined above;

(b) converting the acid moiety in the compound of formula IB to a acidhalide;

(c) reacting the acid halide with a haloaniline or ahaloamino-heterocycle to form a compound having formula IC:

wherein Z¹ is a halogen and A is as defined above;

(d) coupling the compound of formula IC with a compound H—B to give acompound having formula ID:

(e) removing the protecting group from Compound ID and reacting theresulting acid moiety with a C-isocyanate to form a compound of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions are used, unless otherwise described: halo isfluoro, chloro, bromo, or iodo. Alkyl, alkoxy, alkenyl, alkynyl, etc.denote both straight and branched groups; but reference to an individualradical such as “propyl” embraces only the straight chain radical, abranched chain isomer such as “isopropyl” being specifically referredto.

The term “alkyl” as used herein refers to a straight or branchedhydrocarbon of from 1 to 11 carbon atoms and includes, for example,methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl, n-hexyl, and the like. The alkyl group can also besubstituted with one or more of the substituents selected from loweralkoxy, lower thioalkoxy, halogen, nitro, cyano, oxo, thio, —OH, —SH,—F, —CF₃, —OCF₃, —NO₂, —CO₂H, —CO₂C₁-C₆ alkyl, —NH₂, —NHC₁-C₆ alkyl,

—CONR⁸R⁹, or —N(C₁-C₆alkyl)₂. Preferred alkyl groups have from 1 to 6carbon atoms (C₁-C₆ alkyl).

The term “(C₁-C₆)alkyl” as used herein refers to a subset of alkyl whichmeans a straight or branched hydrocarbon radical having from 1 to 6carbon atoms and includes, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl,and the like. Sometimes herein lower alkyl is referred to as“C₁-C₆alkyl.”

The term “(C₁-C₆)hydroxyalkyl” or “hydroxy(C₁-C₆)alkyl” as used hereinmeans a straight or branched alcohol having from 1 to 6 carbon atoms andincludes, for example, hydroxymethyl, hydroxyethyl, hydroxy-propyl andthe like.

The term “(C₂-C₆)alkenyl” means a straight or branched unsaturatedhydrocarbon radical having from 2 to 12 carbon atoms and includes, forexample, ethenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl,2-pentenyl, 3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl,3-heptenyl, 1-Octenyl, 1-nonenyl, 1-decenyl, 1-undecenyl, 1-dodecenyl,and the like.

The term “alkylene” as used herein refers to a divalent group derivedfrom a straight or branched chain saturated hydrocarbon having from 1 to10 carbon atoms by the removal of two hydrogen atoms, for examplemethylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene,2,2-dimethylpropylene, and the like. The alkylene groups of thisinvention can be optionally substituted. The alkylene group can also besubstituted with one or more of the substituents selected from loweralkyl, lower alkoxy, lower thioalkoxy, halogen, nitro, cyano, oxo, thio,—OH, —SH, —F, —CF₃, —OCF₃, —NO₂, —CO₂H, —CO₂C₁-C₆ alkyl, —NH₂, —NHC₁-C₆alkyl,

—CONR⁸R⁹, or —N(C₁-C₆alkyl)₂. Preferred alkylene groups have from 1 to 6carbon atoms (C₁-C₆ alkyl).

The term “heteroatom” as used herein represents oxygen, nitrogen, orsulfur (O, N, or S) as well as sulfoxyl or sulfonyl (SO or SO₂), unlessotherwise indicated. It is to be understood that alkyl chainsinterrupted by one or more heteroatoms means that a carbon atom of thechain is replaced with a heteroatom having the appropriate valency.Preferably, an alkyl chain is interrupted by 1 to 4 heteroatoms and thattwo adjacent carbon atoms are not both replaced. Examples of such groupsinclude methoxymethyl, 3-thiomethylpropyl, and2-thiomethoxyethoxymethyl.

The term “hetero(C₁-C₆)alkyl” as used herein, refers to an alkyl groupthat includes one or more heteroatoms such as oxygen, sulfur, ornitrogen (with valence completed by hydrogen or oxygen) in the carbonchain or terminating the carbon chain.

The term “hydrocarbon chain” as used herein refers to a straighthydrocarbon of from 2 to 6 carbon atoms. The hydrocarbon chain isoptionally substituted with one or more substituents selected from loweralkyl, lower alkoxy, lower thioalkoxy, halogen, nitro, cyano, oxo, thio,—OH, —SH, —F, —CF₃, —OCF₃, —NO₂, —CO₂H, —CO₂C₁-C₆ alkyl, —NH₂, —NHC₁-C₆alkyl,

—CONR⁸R⁹, or —N(C₁-C₆alkyl)₂.

The term “hydrocarbon-heteroatom chain” as used herein refers to ahydrocarbon chain wherein one or more carbon atoms are replaced with aheteroatom. The hydrocarbon-heteroatom chain is optionally substitutedwith one or more substituents selected from lower alkyl, lower alkoxy,lower thioalkoxy, halogen, nitro, cyano, oxo, thio,

—OH, —SH, —F, —CF₃, —OCF₃, —NO₂, —CO₂H, —CO₂C₁-C₆ alkyl, —NH₂, —NHC₁-C₆alkyl, —CONR⁸R⁹, or —N(C₁-C₆alkyl)₂.

The term “heteroalkylene” as used herein, refers to an alkylene radicalas defined above that includes one or more heteroatoms such as oxygen,sulfur, or nitrogen (with valence completed by hydrogen or oxygen) inthe carbon chain or terminating the carbon chain.

The term “(C₃-C₇)cycloalkyl” means a cyclopropyl, cyclobutyl,cylopentyl, cyclohexyl, or cycloheptyl ring, respectively. The(C₃-C₇)cycloalkyl ring may be optionally substituted with one or moresubstituents selected from lower alkyl, lower alkoxy, lower thioalkoxy,halogen, nitro, cyano, oxo, thio,

—OH, —SH, —F, —CF₃, —OCF₃, —NO₂, —CO₂H, —CO₂C₁-C₆ alkyl, —NH₂, —NHC₁-C₆alkyl, —CONR⁸R⁹, or —N(C₁-C₆alkyl)₂.

The term “halo(C₁-C₆)alkyl” as used herein means a lower alkyl radical,as defined above, bearing at least one halogen substituent, for example,chloromethyl, fluoroethyl, or trifluoromethyl, and the like. Haloalkylcan also include perfluoroalkyl wherein all hydrogens of a loweralkylgroup are replaced with fluorides.

The term “heterocycle” means a saturated or unsaturated mono- orpolycyclic (i.e. bicyclic) fused, bridged, or spiro bicyclicheterocyclic ring system ring incorporating one or more (i.e. 1-4)heteroatoms selected from N, O, and S. It is to be understood that aheterocycle is optionally substituted with —OH, —O(alkyl), SH, S(alkyl),amine, halogen, acid, ester, amide, amidine, alkyl ketone, aldehyde,nitrile, fluoroalkyl, nitro, sulphone, sulfoxide or C1-6 alkyl.Monocyclic heterocyclic rings contain from about 3 to 12 ring atoms,with from 1 to 5 heteroatoms selected from N, O, and S, and preferablyfrom 3 to 7 member atoms, in the ring. Bicyclic heterocyclics containfrom 7 to 17 member atoms, preferably 7 to 12 member atoms, in the ring.Bicyclic heterocyclics contain from about 7 to about 17 ring atoms,preferably from 7 to 12 ring atoms. Bicyclic heterocyclics rings may befused, spiro, or bridged ring systems. Examples of heterocyclic groupsinclude cyclic ethers (oxiranes) such as ethyleneoxide, tetrahydrofuran,dioxane, and substituted cyclic ethers, wherein the substituents arethose described above for the alkyl and cycloalkyl groups. Typicalsubstituted cyclic ethers include propyleneoxide, phenyloxirane (styreneoxide), cis-2-butene-oxide(2,3-dimethyloxirane),3-chlorotetrahydrofuran, 2,6-dimethyl-1,4-dioxane, and the like.Heterocycloalyl groups containing nitrogen are groups such aspyrrolidine, piperidine, piperazine, tetrahydrotriazine,tetrahydropyrazole, and substituted groups such as 3-aminopyrrolidine,4-methylpiperazin-1-yl, and the like. Typical sulfur containingheterocycles include tetrahydrothiophene, dihydro-1,3-dithiol-2-yl, andhexahydrothiepin-4-yl. Other commonly employed heterocycles includedihydro-oxathiol-4-yl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl,tetrahydro-dioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl,tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl,tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl,octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocyclescontaining sulfur, the oxidized sulfur heterocycles containing SO or SO₂groups are also included. Examples include the sulfoxide and sulfoneforms of tetrahydrothiophene.

The term “aryl” as used herein refers to an aromatic ring which isunsubstituted or optionally substituted by 1 to 4 substituents selectedfrom lower alkyl, lower alkoxy, lower thioalkoxy, halogen, nitro, cyano—OH, —SH, —F, —CF₃, —OCF₃, —NO₂,

—CO₂H, —CO₂C₁-C₆ alkyl, —NH₂, —NHC₁-C₆ alkyl, —CONR⁸R⁹, —, SO₂alkyl,—SO₂NH₂, or —N(C₁-C₆alkyl)₂. Examples include, but are not limited tophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl,3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 2-chloro-3-methylphenyl, 2-chloro-4-methylphenyl,2-chloro-5-methylphenyl, 3-chloro-2-methylphenyl,3-chloro-4-methylphenyl, 4-chloro-2-methylphenyl,4-chloro-3-methylphenyl, 5-chloro-2-methylphenyl, 2,3-dichlorophenyl,2,5-dichlorophenyl, 3,4-dichlorophenyl, 2,3-dimethylphenyl,3,4-dimethylphenyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl,imidazoyl, pyrazinyl, oxazolyl, thiazolyl, naphthyl, benzothienyl,benzofuranyl, indolyl, quinolinyl, isoquinolinyl, and quinazolinyl, andthe like.

The term “aralkyl” as used herein refers to an alkyl radical to which isappended an aryl group. Representative arylalkyl groups include benzyl,phenylethyl, hydroxybenzyl, fluorobenzyl, fluorophenylethyl, and thelike. The arylalkyl groups of this invention can be optionallysubstituted.

The term “arylene” as used herein refers to a divalent group derivedfrom an aromatic ring. The arylene group can also be substituted withone or more of the substituents listed above for aryl.

The term “heteroaryl” means an aromatic cyclic or fused polycyclic ringsystem having from 1 to 8 heteroatoms selected from N, O, and S. Theheteroaryl groups or fused heteroaryl groups may be unsubstituted orsubstituted by 1 to 3 substituents selected from those described abovefor alkyl, alkenyl, and alkynyl, for example, cyanothienyl andformylpyrrolyl.

Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-,or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl,tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or5-pyrazinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl.

Aromatic fused heteroaryl groups of from 8 to 20 atoms include but arenot limited to 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-,6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-,6-, or 7-imidazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-,6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinoliyl,1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinoliyl, 1-, 4-, 5-, 6-, 7-, or8-phthalazinyl, 2-, 3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-,or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-4aH carbazolyl, 1-, 2-,3-, 4-, 5-, 6-, 7-, or 8-carbzaolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthridinyl, 1-,2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-,or 9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenathrolinyl, 1-,2-, 3-, 4-, 6-, 7-, 8-, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-,or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or10-phenoxazinyl, 2-,3-,4-,5-,6-,or 1-,3-,4-,5-,6-,7-,8-,9-,or10-benzisoqinolinyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-,6-, 7-, 8-, 9-, 10-, or 11-7H-pyrazino[2,3-c]carbazolyl,2-, 3-, 5-, 6-,or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3-, or 5-1H-pyrazolo[4,3d]-oxazolyl,2-, 4-, or 5-4H-imidazo[4,5-d]thiazolyl, 3-, 5-, or8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5-, or 6-imidazo[2,1-b]thiazolyl,1-, 3-, 6-, 7-, 8-, or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-,8-, 9-, 10, or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6-, or7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-, 4-,5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or11-1H-pyrrolo[1,2-b][2]benzazapinyl. Typical fused heteroary groupsinclude, but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl,1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 5-, 6-, or7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or7-benzothiazolyl.

Other heteroaryl groups include the following groups wherein “

” indicates the point of attachment, and any of which may be substitutedas provided above.

The term “monocyclic heteroarylene” as used herein refers to a divalentgroup derived from a monocyclic heteroaryl. The arylene group can alsobe substituted with one or more of the substituents listed above foraryl.

The term “cycloalkenyl” means a cycloalkyl group having one or morecarbon-carbon double or triple bond. Example includes cyclobutene,cyclopentene, cyclohexene, cycloheptene, cyclobutadiene,cyclopentadiene, and the like.

The symbol

means a bond. If an asymetric carbon is created by such a bond, aparticular stereochemistry is not to be implied.

The symbol

means a double bond.

The symbol

indicates covalent points of attachment.

The following abbreviations are used herein:

-   -   HOAc=Acetic acid    -   DCM=Dichlommetbane    -   TFA=Trifluoroacetic acid    -   THF=tetrahydrofuran    -   Me=Methyl    -   APCI=Atmospheric pressure chemical ionization    -   Et=Ethyl    -   EtOAc=Ethyl acetate    -   MeOH=Methanol    -   HPLC=High Pressure Liquid Chromatography

When a bond to a substituent is shown to cross the bond connecting 2atoms in a ring, then such substituent may be bonded to any atom in thering, provided the atom will accept the substituent without violatingits valency. When there appears to be several atoms of the substituentthat may bond to the ring atom, then it is the first atom of the listedsubstituent that is attached to the ring.

When a bond from a substituent is shown to cross the bond connecting 2atoms in a ring of the substituent, then such substituent may be bondedfrom any atom in the ring that is available.

When a bond is represented by a line such as

this is meant to represent that the bond may be absent or present,provided that the resultant compound is stable and of satisfactoryvalency.

The term “patient” means all mammals including humans. Examples ofpatients include humans, cows, dogs, cats, goats, sheep, pigs, andrabbits.

A “therapeutically effective amount” is an amount of a compound of thepresent invention that when administered to a patient ameliorates asymptom of thrombotic disorders, venous thrombosis, arterial thrombosis,pulmonary embolism, myocardial infarction, cerebral infarction,restenosis, cancer, angina, diabetes, atrial fibrillation, or heartfailure. A therapeutically effective amount of a compound of the presentinvention can be easily determined by one skilled in the art byadministering a quantity of a compound to a patient and observing theresult. In addition, those skilled in the art are familiar withidentifying patients having thrombotic disorders, venous thrombosis,arterial thrombosis, pulmonary embolism, myocardial infarction, cerebralinfarction, restenosis, cancer, angina, diabetes, atrial fibrillation,or heart failure.

The term “pharmaceutically acceptable salts, esters, amides, andprodrugs” as used herein refers to those carboxylate salts, amino acidaddition salts, esters, amides, and prodrugs of the compounds of thepresent invention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of patients without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use,as well as the zwitterionic forms, where possible, of the compounds ofthe invention. The term “salts” refers to the relatively non-toxic,inorganic and organic acid addition salts of compounds of the presentinvention. These salts can be prepared in situ during the finalisolation and purification of the compounds or by separately reactingthe purified compound in its free base form with a suitable organic orinorganic acid and isolating the salt thus formed.

In some situations, compounds of the invention may exist in isomericform; for example, as tautomers, enantiomers, or diasteromers. Somecompounds may exhibit polymorphism. All tautomers, enantiomers, anddiasteromers are inorporated within the definition of the compounds ofthe invention. It is further to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, orstereoisomeric form, or mixtures thereof, of a compound of theinvention, which possess the useful properties described herein, itbeing well known in the art how to prepare optically active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase) and how to determine activity or cytotoxicity usingthe standard tests described herein, or using other similar tests whichare well known in the art.

Certain compounds of the present invention can exist in unsolvated formas well as solvated form including hydrated form. In general, thesolvated form including hydrated form is equivalent to unsolvated formand is intended to be encompassed within the scope of the presentinvention.

Referring now to a compound of Formula I,

A specific value for G is H, F, or methyl.

A specific value for W¹ is

Other specifc values for W¹ are —CH₂—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—,—CH₂—HC═CH—CH₂—, —CH₂—CH₂CR⁵R⁶—, —CH₂CR⁵R⁶CH₂—, —CH₂—CH₂CR⁷R⁸—,—CH₂CR⁷R⁸CH₂—, —CH₂—C═R⁹CH₂—, —CH₂—CH₂C═R⁹—, —CH₂CH₂CH₂CH₂—,—CH₂—HC═CH—, —CH₂CH₂NR⁵—, —CH₂NR⁵CH₂—, —CH₂CH₂—NH—CH₂—, —CO—CHR⁵—CH₂—,—CO—CH₂—CHR⁵—, —N═CR⁵—CH═, —N═CR⁵—CH₂—, —N═CH—CR⁵═, —O—CHR⁵—CH═,—O—CHR⁵—CH₂—, and —O—CH₂—CR⁵═, wherein R⁵ is —OH, alkyl,halo(C₁-C₆)alkyl, —NR³R⁴, —OR², halo, —CN, —CH₂OR², —CH₂—NR³R⁴, aryl,monocyclic heteroaryl, alkylaryl, —CONR³R⁴, —COR², halo(C₁-C₆)alkyl, or—CO₂R²; R⁶ is H, alkyl, aralkyl, aryl, or monocyclic heteroaryl; R⁷ andR⁸ are each independently halo; and R⁹ is ═O or ═NOR²;

A specific value for A is is phenyl. Another specific value for A ispyridyl. Other specifc values for A include the following:

wherein

indicate points of attachment, and halo, (C₁-C₆)alkyl, andhalo(C₁-C₆)alkyl are as defined earlier in the definitions section.

A specific value for C is phenyl. Another specifc value for C ispyridyl. Other specifc values for C include ortho- and para-halo phenyl,ortho, para-dihalophenyl, ortho, meta-dihalophenyl,para-(C₁-C₆)alkoxyphenyl, para-(C₁-C₆)alkylphenyl, and meta-halo,para-(C₁-C₆)alkylphenyl.

One specific value for B is

wherein

indicates the point of attachment; Q is NH or is absent; and wherein R¹is OH, —O—(C₁-C₆)alkyl, or NR^(3′)R^(4′), wherein R^(3′) and R^(4′) areindependently H, (C₁-C-₆)alkyl, or are joined together to form aoptionally substituted saturated or unsaturated 5 to 7 membered ring.

Another specific value for B is phenyl or phenyl which is substituted atan ortho position with formyl, H₂NSO₂, MeSO₂, MeSO, MeS,(C₁-₆)alkoxycarbonyl, cyano, H₂N—CH₂—, HN—(C₁-C₆)alkyl-CH₂—,(C₁-C₆)alkyl₂N—CH₂—.

Another specific value for B is pyridyl or pyridyl substituted asprovided in the previous postion.

Another specific value for B is

wherein

indicates the point of attachment.

Another specific value for B is

wherein

indicates the point of attachment and which is an optionally substituted4, 5, 6 or 7-membered ring. When B is

R^(x) and R^(y) can be H, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)carboxyalkyl, or taken together can be O═. X^(III) can be CH₂,CH—OH, CH—CO₂(C₁-C₆)alkyl, O, S, NH, or N(C₁-C₆)alkyl, provided thatwhen R^(x) and R^(y) taken together are O═, X^(III) is CH₂.

Another specific value for B is

or a tautomer thereof such as

When B is

or a tautomer thereof, Y^(II) can be CH₂, CH(C₁-C₆)alkyl, C—CH₂OH,C—CH₂O—(C₁-C₆)alkyl, NH, or N(C₁-C₆)alkyl. R¹⁸ is H, (C₁-C₆)alkyl,hydroxymethyl, CH₂O—(C₁-C₆)alkyl, or NR³R⁴.

Another specific value for B is a 5-membered heteroaryl ting whichcontains at least one nitrogen atom such as imidazolyl, pyrazolyl,triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, oxazolyl, isoxazolyl,thiazolyl, or isothiazolyl, any of which may be optionally substitutedwith halo, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, CH₂O—(C₁-C₆)alkyl, orhalo(C₁-C₆)alkyl. B can also be

,wherein

indicates the point of attachment; X^(a), Y^(a), and Z^(a) are eachindependently CR^(c) or N, wherein R^(c) is H or (C₁-C₆)alkyl; and

R¹⁸ is H, (C₁-C₆)alkyl, hydroxymethyl, CH₂O—(C₁-C₆)alkyl, or NR³R⁴.

Another specific value for B is

wherein

indicates the point of attachment. When B is

J₁, J₂, J₃, and J₄ can each be C, or one or more of J₁, J₂, J₃, or J₄can be N. R¹⁹, R²⁰, R²¹, and R²² are each independently H, halo,hydroxy, NH₂, NR²³R²⁴, NO₂, SH, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, or(C₁-C₆)alkoxy, wherein R²³ and R²⁴ are each independently H,(C₁-C₆)alkyl, aralkyl, aryl, monocyclic heteroaryl, alkoxycarbonyl,aralkoxycarbonyl, —SO₂alkyl, or joined together to form a saturated orunsaturated 3 to 7 membered ring. Alternatively, R¹⁹ and R²⁰, R²⁰ andR²¹, or R²¹ and R²², can be together with the carbons to which they areattached to form a 5, 6, or seven membered saturated or unsaturatedcycloalkyl or heterocycloalkyl ring, or an aryl or heteroaryl ring. Whenany of J₁, J₂, J₃, or J₄ is N, R¹⁹, R²⁰, R²¹ or R²², respectively, isabsent at that position. Thus, specifc values for B include

wherein

indicates the point of attachment; and R¹⁹, R²⁰, and R²¹, R²² are eachindependently H, halo, hydroxy, NH₂, NR²³R²⁴, NO₂, SH, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl,or (C₁-C₆)alkoxy, wherein R²³ and R²⁴ are each independently H,(C₁-C₆)alkyl, aralkyl, aryl, monocyclic heteroaryl, alkoxycarbonyl,aralkoxycarbonyl, —SO₂alkyl, or joined together to form a saturated orunsaturated 3 to 7 membered ring, or R¹⁹ and R²⁰, R²⁰ and R²¹, or R²¹and R²², together with the carbons to which they are attached, form a 5,6, or seven membered saturated or unsaturated cycloalkyl orheterocycloalkyl ring, or an aryl or heteroaryl ring.

Reference will now be made to a compound of Formula II.

In

- - ” is a bond or is absent. A specifc value for X^(II) is CH₂. Otherspecifc values for X^(II) include CH, NH and N. Specific values for R¹⁰and R¹¹ include H, hydroxy, methoxy, ethoxy, cyano, trifluoromethyl,fluoro, NH₂, carboethoxy,

wherein

indicates the point of attachment. Also, R¹⁰ and R¹¹ can be takentogether to form ═O or ═NOH. Thus, specific values for

A specific value for G is H, F, or methyl.

A specific value for C is phenyl. Another specifc value for C ispyridyl. Other specifc values for C include ortho- and para-halo phenyl,ortho, para-dihalophenyl, ortho, meta-dihalophenyl,para(C₁-C₆)alkoxyphenyl, para-(C₁-C₆)alkylphenyl, and meta-halo,para-(C₁-C₆)alkylphenyl.

A specific value for A is is phenyl. Another specific value for A ispyridyl. Other specifc values for A include the following:

wherein

indicate points of attachment, and halo, (C₁-C₆)alkyl, andhalo(C₁-C₆)alkyl are as defined earlier in the definitions section.

One specific value for B is

wherein

indicates the point of attachment; Q is NH or is absent; and wherein R¹is OH, —O—(C₁-C₆)alkyl, or NR^(3′)R^(4′), wherein R^(3′) and R^(4′) areindependently H, (C₁-C-₆)alkyl, or are joined together to form aoptionally substituted saturated or unsaturated 5 to 7 membered ring.

Another specific value for B is phenyl or phenyl which is substituted atan ortho position with formyl, H₂NSO₂, MeSO₂, MeSO, MeS,(C₁-₆)alkoxycarbonyl, cyano, H₂N—CH₂—, HN—(C₁-C₆)alkyl-CH₂—,(C₁-C₆)alkyl₂N—CH₂—.

Another specific value for B is pyridyl or pyridyl substituted asprovided in the previous postion.

Another specific value for B is

wherein

indicates the point of attachment.

Another specific value for B is

wherein

indicates the point of attachment.and which is an optionally substituted4, 5, 6 or 7-membered ring. When B is

R^(x) and R^(y) can be H, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)carboxyalkyl, or taken together can be O═. X^(III) can be CH₂,CH—OH, CH—CO₂(C₁-C₆)alkyl, O, S, NH, or N(C₁-C₆)alkyl, provided thatwhen R^(x) and R^(y) taken together are O═, X^(III) is CH₂.

Another specific value for B is

or a tautomer thereof such as

or a tautomer thereof, Y^(II) can be CH₂, CH(C₁-C₆)alkyl, C—CH₂OH,C—CH₂O—(C₁-C₆)alkyl, NH, or N(C₁-C₆)alkyl. R⁸ is H, (C₁-C₆)alkyl,hydroxymethyl, CH₂O—(C₁-C₆)alkyl, or NR³R⁴.

Another specific value for B is a 5-membered heteroaryl ting whichcontains at least one nitrogen atom such as imidazolyl, pyrazolyl,triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, oxazolyl, isoxazolyl,thiazolyl, or isothiazolyl, any of which may be optionally substitutedwith halo, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, CH₂O—(C₁-C₆)alkyl, orhalo(C₁-C₆)alkyl. B can also be

wherein

indicates the point of attachment; X^(a), Y^(a), and Z^(a) are eachindependently CR^(c) or N, wherein R^(c) is H or (C₁-C₆)alkyl; and

R¹⁸ is H, (C₁-C₆)alkyl, hydroxymethyl, CH₂O—(C₁-C₆)alkyl, or NR³R⁴.

Another specific value for B is

wherein

indicates the point of attachment. When B is

J₁, J₂, J₃, and J₄ can each be C, or one or more of J₁, J₂, J₃, or J₄can be N. R¹⁹, R²⁰ , R²¹, and R²² are each independently H, halo,hydroxy, NH₂, NR²³R²⁴, NO₂, SH, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, or(C₁-C₆)alkoxy, wherein R²³ and R²⁴ are each independently H,(C₁-C₆)alkyl, aralkyl, aryl, monocyclic heteroaryl, alkoxycarbonyl,aralkoxycarbonyl, —SO₂alkyl, or joined together to form a saturated orunsaturated 3 to 7 membered ring. Alternatively, R¹⁹ and R²⁰, R²⁰ andR²¹, or R²¹ and R²², can be together with the carbons to which they areattached to form a 5, 6, or seven membered saturated or unsaturatedcycloalkyl or heterocycloalkyl ring, or an aryl or heteroaryl ring. Whenany of J₁, J₂, J₃, or J₄ is N, R¹⁹, R²⁰, R²¹ or R²², respectively, isabsent at that position. Thus, specifc values for B include

wherein

indicates the point of attachment; and R¹⁹, R²⁰, and R²¹, R²² are eachindependently H, halo, hydroxy, NH₂, NR²³R²⁴, NO₂, SH, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl,or (C₁-C₆)alkoxy, wherein R²³ and R²⁴ are each independently H,(C₁-C₆)alkyl, aralkyl, aryl, monocyclic heteroaryl, alkoxycarbonyl,aralkoxycarbonyl, —SO₂alkyl, or joined together to form a saturated orunsaturated 3 to 7 membered ring, or R¹⁹ and R²⁰, R²⁰ and R²¹, or R²¹and R²², together with the carbons to which they are attached, form a 5,6, or seven membered saturated or unsaturated cycloalkyl orheterocycloalkyl ring, or an aryl or heteroaryl ring.

Reference will now be made to a compound of Formula III:

In

is a bond or is absent. A specifc value for X^(II) is CH₂. Other specifcvalues for X^(II) include CH, NH and N. Specific values for R¹⁰ and R¹¹include H, hydroxy, methoxy, ethoxy, cyano, trifluoromethyl, fluoro,NH₂, carboethoxy,

wherein

indicates the point of attachment. Also, R¹⁰ and R¹¹ taken together canbe ═O or ═NOH. Thus, specific values for

In

Z is N, CH, C(C₁-C₆)alkyl, C(C₁-C₆)alkoxy, or C-halo. R12 and R13 areeach independently H, halo, (C₁-C₆)alkyl, or (C₁-C₆)alkoxy. Specificvalues for

therefore include phenyl, pyridyl, para-chlorophenyl, para-fluorophenyl,para-bromophenyl, para-methoxyphenyl, para-toluyl, para-chloropyridyl,ortho, para-difluorophenyl, meta, para-difluorophenyl, and meta fluoro,paratoluyl.

A specific value for G is H, F, or methyl.

A specific value for A is is phenyl. Another specific value for A ispyridyl. Other specifc values for A include the following:

wherein

indicate points of attachment, and halo, (C₁-C₆)alkyl, andhalo(C₁-C₆)alkyl are as defined earlier in the definitions section.

One specific value for B is

wherein

indicates the point of attachment; Q is NH or is absent; and wherein R¹is OH, —O—(C₁-C₆)alkyl, or NR^(3′)R^(4′), wherein R^(3′) and R^(4′) areindependently H, (C₁-C-₆)alkyl, or are joined together to form aoptionally substituted saturated or unsaturated 5 to 7 membered ring.

Another specific value for B is phenyl or phenyl which is substituted atan ortho position with formyl, H₂NSO₂, MeSO₂, MeSO, MeS,(C₁-₆)alkoxycarbonyl, cyano, H₂N—CH₂—, HN—(C₁-C₆)alkyl-CH₂—,(C₁-C₆)alkyl₂N—CH₂—.

Another specific value for B is pyridyl or pyridyl substituted asprovided in the previous postion.

Another specific value for B is

wherein

indicates the point of attachment.

Another specific value for B is

wherein

indicates the point of attachment.and which is an optionally substituted4, 5, 6 or 7-membered ring. When B is

R^(x) and R^(y) can be H, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)carboxyalkyl, or taken together can be O═. X^(III) can be CH₂,CH—OH, CH—CO₂(C₁-C₆)alkyl, O, S, NH, or N(C₁-C₆)alkyl, provided thatwhen R^(x) and R^(y) taken together are O═, X^(III) is CH₂.

Another specific value for B is

or a tautomer thereof such as

When B is

or a tautomer thereof, Y^(II) can be CH₂, CH(C₁-C₆)alkyl, C—CH₂OH,C—CH₂O—(C₁-C₆)alkyl, NH, or N(C₁-C₆)alkyl. R¹⁸ is H, (C₁-C₆)alkyl,hydroxymethyl, CH₂O—(C₁-C₆)alkyl, or NR³R⁴.

Another specific value for B is a 5-membered heteroaryl ting whichcontains at least one nitrogen atom such as imidazolyl, pyrazolyl,triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, oxazolyl, isoxazolyl,thiazolyl, or isothiazolyl, any of which may be optionally substitutedwith halo, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, CH₂O—(C₁-C₆)alkyl, orhalo(C₁-C₆)alkyl. B can also be

wherein

indicates the point of attachment; X^(a), Y^(a), and Z^(a) are eachindependently CR^(c) or N, wherein R^(c) is H or (C₁-C₆)alkyl; and

R¹⁸ is H, (C₁-C₆)alkyl, hydroxymethyl, CH₂O—(C₁-C₆)alkyl, or NR³R⁴.

Another specific value for B is

wherein

indicates the point of attachment. When B is

J₁, J₂, J₃, and J₄ can each be C, or one or more of J₁, J₂, J₃, or J₄can be N. R¹⁹, R²⁰, R²¹, and R²² are each independently H, halo,hydroxy, NH₂, NR²³R²⁴, NO₂, SH, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, or(C₁-C₆)alkoxy, wherein R²³ and R²⁴ are each independently H,(C₁-C₆)alkyl, aralkyl, aryl, monocyclic heteroaryl, alkoxycarbonyl,aralkoxycarbonyl, —SO₂alkyl, or joined together to form a saturated orunsaturated 3 to 7 membered ring. Alternatively, R¹⁹ and R²⁰, R²⁰ andR²¹, or R²¹ and R²², can be together with the carbons to which they areattached to form a 5, 6, or seven membered saturated or unsaturatedcycloalkyl or heterocycloalkyl ring, or an aryl or heteroaryl ring. Whenany of J₁, J₂, J₃, or J₄ is N, R¹⁹, R²⁰, R²¹ or R²², respectively, isabsent at that position. Thus, specifc values for B include

wherein

indicates the point of attachment; and R¹⁹, R²⁰, and R²¹, R²² are eachindependently H, halo, hydroxy, NH₂, NR²³R²⁴, NO₂, SH, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl,or (C₁-C₆)alkoxy, wherein R²³ and R²⁴ are each independently H,(C₁-C₆)alkyl, aralkyl, aryl, monocyclic heteroaryl, alkoxycarbonyl,aralkoxycarbonyl, —SO₂alkyl, or joined together to form a saturated orunsaturated 3 to 7 membered ring, or R¹⁹ and R²⁰, R²⁰ and R²¹, or R²¹and R²², together with the carbons to which they are attached, form a 5,6, or seven membered saturated or unsaturated cycloalkyl orheterocycloalkyl ring, or an aryl or heteroaryl ring.

Reference will now be made to a compound of Formula IV:

In

is a bond or is absent. A specifc value for X^(II) is CH₂. Other specifcvalues for X^(II) include CH, NH and N. Specific values for R¹⁰ and R¹¹include H, hydroxy, methoxy, ethoxy, cyano, trifluoromethyl, fluoro,NH₂, carboethoxy,

MeSO₂N—

wherein

indicates the point of attachment. Also, R¹⁰ and R¹¹ taken together canbe ═O or ═NOH. Thus, specific values for

In

Z is N, CH, C(C₁-C₆)alkyl, C—(C₁-C₆)alkoxy, or C-halo. R¹² and R¹³ areeach independently H, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy. Specific valuesfor

therefore include phenyl, pyridyl, parachlorophenyl, parafluorophenyl,parabromophenyl, paramethoxyphenyl, paratoluyl, parachloropyridyl,ortho, para-difluorophenyl, meta, para-difluorophenyl, and meta fluoro,paramethyl phenyl.

In

X and Y are each independantly N, CH, C-halo, C(C₁-C₆)alkyl,C-halo(C₁-C₆)alkyl, or C-heterocycloalkyl. R¹⁴ and R¹⁵ are eachindependently H, halo, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, orheterocycloalkyl. Specific values for

A specific value for G is H, F, or methyl.

One specific value for B is

wherein

indicates the point of attachment; Q is NH or is absent; and whereinR^(1′) is OH, —O—(C₁-C₆)alkyl, or NR^(3′)R^(4′), wherein R^(3′) andR^(4′) are independently H, (C₁-C-₆)alkyl, or are joined together toform a optionally substituted saturated or unsaturated 5 to 7 memberedring.

Another specific value for B is phenyl or phenyl which is substituted atan ortho position with formyl, H₂NSO₂, MeSO₂, MeSO, MeS,(C₁-₆)alkoxycarbonyl, cyano, H₂N—CH₂—, HN—(C₁-C₆)alkyl-CH₂—,(C₁-C₆)alkyl₂N—CH₂—.

Another specific value for B is pyridyl or pyridyl substituted asprovided in the previous postion.

Another specific value for B is

wherein

indicates the point of attachment.

Another specific value for B is

wherein

indicates the point of attachment.and which is an optionally substituted4, 5, 6 or 7-membered ring. When B is

R^(x) and R^(y) can be H, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)carboxyalkyl, or taken together can be O═. X^(III) can be CH₂,CH—OH, CH—CO₂(C₁-C₆)alkyl, O, S, NH, or N(C₁-C₆)alkyl, provided thatwhen R^(x) and R^(y) taken together are O═, X^(III) is CH₂.

Another specific value for B is

or a tautomer thereof such as

When B is

or a tautomer thereof, Y^(II) can be CH₂, CH(C₁-C₆)alkyl, C—CH₂OH,C—CH₂O—(C₁-C₆)alkyl, NH, or N(C₁-C₆)alkyl. R⁸ is H, (C₁-C₆)alkyl,hydroxymethyl, CH₂O—(C₁-C₆)alkyl, or NR³R⁴.

Another specific value for B is a 5-membered heteroaryl ting whichcontains at least one nitrogen atom such as imidazolyl, pyrazolyl,triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, oxazolyl, isoxazolyl,thiazolyl, or isothiazolyl, any of which may be optionally substitutedwith halo, (C₁-C₆)alkyl, hydroxy(C₁-C₆)alkyl, CH₂O—(C₁-C₆)alkyl, orhalo(C₁-C₆)alkyl. B can also be

wherein

indicates the point of attachment; X^(a), Y^(a), and Z^(a) are eachindependently CR^(c) or N, wherein R^(c) is H or (C₁-C₆)alkyl; and

R¹⁸ is H, (C₁-C₆)alkyl, hydroxymethyl, CH₂O—(C₁-C₆)alkyl, or NR³R⁴.

Another specific value for B is

wherein

indicates the point of attachment. When B is

J₁, J₂, J₃, and J₄ can each be C, or one or more of J₁, J₂, J₃, or J₄can be N. R¹⁹, R²⁰, R²¹, and R²² are each independently H, halo,hydroxy, NH₂, NR²³R²⁴, NO₂, SH, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,halo(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, or(C₁-C₆)alkoxy, wherein R²³ and R²⁴ are each independently H,(C₁-C₆)alkyl, aralkyl, aryl, monocyclic heteroaryl, alkoxycarbonyl,aralkoxycarbonyl, —SO₂alkyl, or joined together to form a saturated orunsaturated 3 to 7 membered ring. Alternatively, R¹⁹ and R²⁰, R²⁰ andR²¹ or R²¹ and R²², can be together with the carbons to which they areattached to form a 5, 6, or seven membered saturated or unsaturatedcycloalkyl or heterocycloalkyl ring, or an aryl or heteroaryl ring.

When any of J₁, J₂, J₃, or J₄ is N, R¹⁹, R²⁰, R²¹ or R²², respectively,is absent at that position. Thus, specifc values for B include

wherein

indicates the point of attachment; and R¹⁹, R²⁰, and R²¹, R²² are eachindependently H, halo, hydroxy, NH₂, NR²³, R²⁴, NO₂, SH, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl,or (C₁-C₆)alkoxy, wherein R²³ and R²⁴ are each independently H,(C₁-C₆)alkyl, aralkyl, aryl, monocyclic heteroaryl, alkoxycarbonyl,aralkoxycarbonyl, —SO₂alkyl, or joined together to form a saturated orunsaturated 3 to 7 membered ring, or R¹⁹ and R²⁰, R²⁰ and R²¹, or R²¹and R²², together with the carbons to which they are attached, form a 5,6, or seven membered saturated or unsaturated cycloalkyl orheterocycloalkyl ring, or an aryl or heteroaryl ring.

Reference will now be made to a compound of Formula V:

In

is a bond or is absent. A specifc value for X^(II) is CH₂. Other specifcvalues for X^(II) include CH, NH and N. Specific values for R¹⁰ and R¹¹include H, hydroxy, methoxy, ethoxy, cyano, trifluoromethyl, fluoro,NH₂, carboethoxy,

wherein

indicates the point of attachment. Also, R¹⁰ and R¹¹ taken together canbe ═O or ═NOH. Thus, specific values for

In

Z is N, CH, C(C₁-C₆)alkyl, C—(C₁-C₆)alkoxy, or C-halo. R¹² and R¹³ areeach independently H, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy. Specific valuesfor

parachlorophenyl, parafluorophenyl, parabromophenyl, paramethoxyphenyl,paratoluyl, parachloropyridyl, ortho, para-difluorophenyl, meta,para-difluorophenyl, and meta fluoro, paramethyl phenyl.

In

X and Y are each independantly N, CH, C-halo, C(C₁-C₆)alkyl,C-halo(C₁-C₆)alkyl, or C-heterocycloalkyl. R¹⁴ and R¹⁵ are eachindependently H, halo, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, orheterocycloalkyl. Specific values for

A specific value for G is H, F, or methyl.

In

is absent or is a fused heterocyclic or fused heteroaryl ring, providedthat when

is present, Y′ is C. X′ and Y′ are eaqch independently N, CH, C-halo,C-halo, C—(C₁-C₆)alkyl, C-halo(C₁-C₆)alkyl, C—(C₁-C₆)alkoxy, C—OH,C—SO₂Me, C—SO₂NH₂, C—SOMe, C—SMe, C—CO₂(C₁-C₆)alkyl, C—CN, or C—CH₂NH₂.Specific values for

Reference will now be made to a compound of Formula VI.

In

is a bond or is absent. A specifc value for X^(II) is CH₂. Other specifcvalues for X^(II) include CH, NH and N. Specific values for R¹⁰ and R¹¹include H, hydroxy, methoxy, ethoxy, cyano, trifluoromethyl, fluoro,NH₂, carboethoxy,

wherein

indicates the point of attachment. Also, R¹⁰ and R¹¹ taken together canbe ═O or ═NOH. Thus, specific values for

In

Z is N, CH, C(C₁-C₆)alkyl, C—(C₁-C₆)alkoxy ,or C-halo. R¹² and R¹³ areeach independently H, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy.

Specific values for

therefore include phenyl, pyridyl, parachlorophenyl, parafluorophenyl,parabromophenyl, paramethoxyphenyl, paratoluyl, parachloropyridyl,ortho, para-difluorophenyl, meta, para-difluorophenyl, and meta fluoro,paramethyl phenyl.

In

X and Y are each independantly N, CH, C-halo, C(C₁-C₆)alkyl,C-halo(C₁-C₆)alkyl, or C-heterocycloalkyl. R¹⁴ and R¹⁵ are eachindependently H, halo, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, orheterocycloalkyl.

Specific values for

A specific value for G is H, F, or methyl.

In

Q is NH or is absent. R¹ is OH, —O—(C₁-C-₆)alkyl, (C₃-C-₇)cycloalkyl,(C₃-C-₇)heterocycloalkyl, (C₄-C-₇)cycloalkenyl,(C₄-C-₇)heterocycloalkenyl, aryl, monocyclic heteroaryl, or —NR³R⁴,wherein R³ and R⁴ are independently H, (C₁-C-₆)alkyl, aralkyl, aryl,monocyclic heteroaryl, alkoxycarbonyl, aralkoxycarbonyl, —SO₂alkyl, orjoined together to form a saturated or unsaturated 5 to 7 membered ring.Thus, specifc values for

Reference will now be made to a compound of Formula VII.

In

is a bond or is absent. A specifc value for X^(II) is CH₂. Other specifcvalues for X^(II) include CH, NH and N. Specific values for R¹⁰ and R¹¹include H, hydroxy, methoxy, ethoxy, cyano, trifluoromethyl, fluoro,NH₂, carboethoxy,

wherein

indicates the point of attachment. Also, R¹⁰ and R¹¹ taken together canbe ═O or ═NOH. Thus, specific values for

In

Z is N, CH, C(C₁-C₆)alkyl, C(C₁-C₆)alkoxy, or C-halo. R¹² and R¹³ areeach independently H, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy. Specific valuesfor

therefore include phenyl, pyridyl, parachlorophenyl, parafluorophenyl,parabromophenyl, paramethoxyphenyl, paratoluyl, parachloropyridyl,ortho, para-difluorophenyl, meta, paradifluorophenyl, and meta fluoro,paramethyl phenyl.

In

X and Y are each independantly N, CH, C-halo, C(C₁-C₆)alkyl,C-halo(C₁-C₆)alkyl, or C-heterocycloalkyl. R¹⁴ and R¹⁵ are eachindependently H, halo, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, orheterocycloalkyl. Specific values for

A specific value for G is H, F, or methyl.

In compounds of Formula VII,

is an optionally substituted 4, 5, 6 or 7-membered ring, wherein R^(x)and R^(y) are H, halo, hydroxymethyl, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, orwherein R^(x) and R^(y) are H, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)carboxyalkyl, or taken together are O=. X^(III) is CH₂, CH—OH,CH—CO₂(C₁-C₆)alkyl, O═, S, NH, or N(C₁-C₆)alkyl, provided that whenR^(x) and R^(y) taken together are O═, X^(III) is CH₂. Thus, specifcvalues for

Any of the specifc values for

may be further optionally substituted with one, two or threesubstitutent groups selected from the group consisting of halo,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, or hydroxymethyl.

Reference will now be made to a compound of Formula VIII.

In

is a bond or is absent. A specifc value for X^(II) is CH₂. Other specifcvalues for X^(II) include CH, NH and N. Specific values for R¹⁰ and R¹¹include H, hydroxy, methoxy, ethoxy, cyano, trifluoromethyl, fluoro,NH₂, carboethoxy,

wherein

indicates the point of attachment. Also, R¹⁰ and R¹¹ taken together canbe ═O or ═NOH. Thus, specific values for

In

Z is N, CH, C(C₁-C₆)alkyl, C(C₁-C₆)alkoxy, or C-halo. R¹² and R¹³ areeach independently H, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy. Specific valuesfor

therefore include phenyl, pyridyl, parachlorophenyl, parafluorophenyl,parabromophenyl, paramethoxyphenyl, paratoluyl, parachloropyridyl,ortho, para-difluorophenyl, meta, para-difluorophenyl, and meta fluoro,paramethyl phenyl.

In

X and Y are each independantly N, CH, C-halo, C(C₁-C₆)alkyl,C-halo(C₁-C₆)alkyl, or C-heterocycloalkyl. R¹⁴ and R¹⁵ are eachindependently H, halo, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, orheterocycloalkyl. Specific values for

In compounds of Formula VIII,

can exist in tautomeric form as

Furthermore, in

Y^(II) is CH, CR¹⁸, or N. R¹⁸ is H, (C₁-C₆)alkyl, hydroxymethyl,CH₂O—(C₁-C₆)alkyl, or NR³R⁴, wherein R³ and R⁴ are each independently H,(C₁-C₆)alkyl, aralkyl, aryl, monocyclic heteroaryl, alkoxycarbonyl,aralkoxycarbonyl, —SO₂alkyl, or joined together to form a saturated orunsaturated 3 to 7 membered ring. Thus, specifc values for

include

A specific value for G is H, F, or methyl.

Reference will now be made to a compound of Formula IX.

In

is a bond or is absent. A specifc value for X^(II) is CH₂. Other specifcvalues for X^(II) include CH, NH and N. Specific values for R¹⁰ and R¹¹include H, hydroxy, methoxy, ethoxy, cyano, trifluoromethyl, fluoro,NH₂, carboethoxy,

wherein

indicates the point of attachment. Also, R¹⁰ and R¹¹ taken together canbe ═O or ═NOH. Thus, specific values for

In

Z is N, CH, C(C₁-C₆)alkyl, or C-halo. R¹² and R¹³ are each independentlyH, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy. Specific values for

therefore include phenyl, pyridyl, parachlorophenyl, parafluorophenyl,parabromophenyl, paramethoxyphenyl, paratoluyl, parachloropyridyl,ortho, para-difluorophenyl, meta, para-difluorophenyl, and meta fluoro,paramethyl phenyl.

In

X and Y are each independantly N, CH, C-halo, C(C₁-C₆)alkyl,C-halo(C₁-C₆)alkyl, or C-heterocycloalkyl. R¹⁴ and R¹⁵ are eachindependently H, halo, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl, orheterocycloalkyl. Specific values for

include

In

X^(a), Y^(a), and Z^(a) are each independently CH, CR¹⁸ or N; and R¹⁸ isH, (C₁-C₆)alkyl, hydroxymethyl, CH₂-(C₁-C₆)alkyl, or NR³R⁴, wherein R³and R⁴ are each independently H, (C₁-C₆)alkyl, aralkyl, aryl, monocyclicheteroaryl, alkoxycarbonyl, aralkoxycarbonyl, —SO₂alkyl, or joinedtogether to form a saturated or unsaturated 3 to 7 membered ring. Thus,specific values for

include imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxadiazolyl,thiadiazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl, any ofwhich may be optionally substituted with halo, (C₁-C₆)alkyl,hydroxy(C₁-C₆)alkyl, CH₂O—(C₁-C₆)alkyl, or halo(C₁-C₆)alkyl. Othervalues for

A specific value for G is H, F, or methyl.

Reference will now be made to a compound of Formula X.

In

is a bond or is absent. A specifc value for X^(II) is CH₂. Other specifcvalues for X^(II) include CH, NH and N. Specific values for R¹⁰ and R¹¹include H, hydroxy, methoxy, ethoxy, cyano, trifluoromethyl, fluoro,NH₂, carboethoxy,

wherein

indicates the point of attachment. Also, R¹⁰ and R¹¹ taken together canbe ═O or ═NOH. Thus, specific values for

In

Z is N, CH, C(C₁-C₆)alkyl, —(C₁-C₆)alkoxy, or C-halo. R¹² and R¹³ areeach independently H, halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy. Specific valuesfor

therefore include phenyl, pyridyl, parachlorophenyl, parafluorophenyl,parabromophenyl, paramethoxyphenyl, paratoluyl, parachloropyridyl,ortho, para-difluorophenyl, meta, paradifluorophenyl, and meta fluoro,paramethyl phenyl.

In

J₁, J₂, J₃, and J₄ are each C, or one of J₁, J₂, J₃, and J₄ is N. R¹⁹,R²⁰, R²¹, and R²² are each independently H, halo, hydroxy, NH₂, NR²³R²⁴,NO₂, SH, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, halo(C₁-C₆)alkyl, (C₁-C₆)alkanoyl,(C₁-C₆)alkoxycarbonyl, or (C₁-C₆)alkoxy, wherein R²³ and R²⁴ are eachindependently H, (C₁-C₆)alkyl, aralkyl, aryl, monocyclic heteroaryl,alkoxycarbonyl, aralkoxycarbonyl, —SO₂alkyl, or joined together to forma saturated or unsaturated 3 to 7 membered ring, or R¹⁹ and R²⁰, R²⁰ andR²¹, or R²¹ and R²², together with the carbons to which they areattached, form a 5, 6, or 7 membered saturated or unsaturated cycloalkylor heterocycloalkyl ring, or an aryl or heteroaryl ring. Also, when anyof J₁, J₂, J₃, or J₄ is N, R¹⁹, R²⁰, R²¹ or R²², respectively, is absentat that position. Thus, specifc values for

A specific value for G is H, F, or methyl.

PREPARATION OF COMPOUNDS OF THE INVENTION

Processes and novel intermediates for preparing compounds of formula Iare provided as further embodiments of the invention and are illustratedby the following procedures in which the meanings of the genericradicals are as given above unless otherwise qualified. Certaincompounds of formula I are useful as intermediates for preparing othercompounds of formula I.

It is also noted that compounds of formula I can be prepared usingprotecting groups. It is to be noted that the appropriate use and choiceof protecting groups is well-known by one skilled in the art, and is notlimited to the specific examples below. It is also to be understood thatsuch groups not only serve to protect chemically reactive sites, butalso to enhance solubility or otherwise change physical properties. Agood general reference for protecting group preparation and deprotectionis “Protecting Groups in Organic Synthesis” by T. W. Green and P. G.Wuts. A number of general reactions such as oxidations and reductionsetc. are not shown in detail but can be done by methods understood byone skilled in the art. General transformations are well-reviewed in“Comprehensive Organic Transformation” by Richard Larock, and the series“Compendium of Organic Synthetic Methods” published byWiley-Interscience. In general, the starting materials are obtained fromcommercial sources unless otherwise indicated.

It will be appreciated by those skilled in the art that compounds of theinvention having one or more chiral centers may exist in and be isolatedin optically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, geometric, orstereoisomeric form, or mixtures thereof, of a compound of theinvention, which possess the useful properties described herein, itbeing well known in the art how to prepare optically active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase) and how to determine activity or cytotoxicity usingthe standard tests described herein, or using other similar tests whichare well known in the art.

It will be further appreciated by the skilled artisan that the followingschemes depict the synthesis of some compounds of the invention. It isto be understood, however, that compounds of the invention other thanthose specifically disclosed can be prepared using the strategiesdepicted in the schemes.

One method for making compounds of the invention is disclosed inScheme 1. The route is useful for a wide variety of starting materialswith variable W¹ groups, provided the appropriate protecting group isutilized, if necessary. The scheme is also employed for both racemicmixtures and enantiomerically pure compounds. The method comprisesreacting an amino acid having Formula A with a reagent capable offorming a protecting group on the amino group of an amino acid to formcompound with Formula B. In Scheme 1, p¹ is a protecting group and W¹ isthe same as defined above. The compound of Formula B is next convertedinto an acid halide. Alternatively the carboxyliz acid may be activatedby a number of coupling reagents, but not limited to, such as BOP, HATU,EEDQ, or CDI. The acid halide is then reacted with a haloaniline or ahaloaminoheterocycle to form a halide having Formula D, where Y¹ is ahalogen and A is as defined above. The compound with Formula D is thensubjected to a coupling reaction with a compound having B to give acompound of Formula E. The protecting group is then removed fromcompound E and the resulting compound reacted with an isocyanate havingC to from a compound of Formula I. Finally, as relating to Scheme 1 andsubsequent schemes, it is to be noted that compounds of the inventionwherein G has any of the provided meanings other than H can be easilyprepared by techniques available to the skilled artisan. For example,compounds wherein G is alkyl can be prepared by alkylation of I, or byalkylation of a corresponding ester of A, B D, or E.

Scheme 2 provides a more detailed approach to the preparation ofcompounds of the invention. The synthetic route starts by protecting anamino acid A with di-tert-butyl dicarbonate in tetrahydrofuran with 2MNaOH as the base. The resulting BOC-protected amino acid B-1 isconverted into the acid chloride using oxalyl chloride, with pyridineadded to prevent deprotection. The acid chloride or acid is thenimmediately reacted with a bromoaniline or bromoaminoheterocycle ofchoice. The resulting bromide is then typically subjected to a Suzukicoupling with a boronic acid, although other coupling conditions may beused to provide D-1. Compound D-1 is then deprotected with 33%trifluoroacetic acid in dichloromethane and allowed to reacted with anisocyanate in the presence of an amine base such as triethylamine intetrahydrofuran or the like. This route is useful for preparingcompounds containing biaryl A-B groups; i.e., where both A and B arearyl.

Another method of making compounds of the invention is depicted inScheme 3. The route summarized in Scheme 3 is useful for synthesizing awide variety of A-B groups. The chemistry is similar to Scheme 1, butthe second step (i.e., the conversion of B to D) introduces differentsubstituted aniline or aminoheterocycle. By selecting an appropriatelysubstituted aniline or aminoheteroaryl group, a wide variety of B groupscan be introduced. For example, with Z is a cyano group, thecorresponding imidazole and imidazoline compounds can be made usingtechniques known to the skilled artisan. When Z is a methyl ester or thelike, the corresponding amides and ketones can be synthesized via anumber of methods available to the skilled artsian. For example, anamide is prepared by hydrolyzing the ester with lithium hydroxide,treating the resulting carboxylic acid with a typical peptide couplingreagent such as HATU, followed by introduction of the desired amine.

Compounds of the invention may also be prepared as provided in Scheme 4.Thus, a mixture of F (where Z is a halide and Y is an amino or nitrogroup), B (where B is a nitrogen-containing ring, an amine or amide),K₃PO₄, CuI, and trans-diaminocyclohexane is heated in dioxane at refluxto obtain compound G. In the case where Y is a nitro group, the moietyis reduced to the amino group with RaNi and EtOH under a hydrogenatmosphere. The appropriate aniline G, EEDQ, triethylamine andcarboxylic acid H are heated at reflux in chloroform to produce J.Finally, a solution of compound J, TFA and DCM is stirred at roomtemperature for I h and then concentrated under reduced pressure. Theresulting oil is dissolved in THF and cooled to 0° C. followed by theaddition of triethylamine and the appropriate isocyanate to produceinvention compound K.

Scheme 5 provides an approach to compounds of the invention whereinX^(II) in

(c.f., Formulas II-X), is N and

is a bond. Thus, Aniline M is converted to an acrylamide N by theaddition of acryoyl chloride and a base, such as saturated sodiumbicarbonate, in a solvent such as ethyl acetate at room temperature.Alternatively, the aniline may be converted to N by the addition of anacrylic acid and adding a coupling reagent such asdicyclohexylcarbodi-imide (DCC),O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), or EEDQ. The acrylamide N is added an excessof trimethylsilyl diazomethane in a solvent such as ethyl acetate ordichloromethane. The resulting dihydropyrazole O may then be treatedwith an isocyanate, in the presence of base such as pyridine ortriethylamine, in a solvent such as dichloromethane, to afford compoundP.

An alternative approach to molecules wherein X^(II) in

(c.f., Formulas II-X), is N and “- - - -” is a bond is provided inScheme 5.2. The chemistry for the preparation of compounds Q-T issimilar to that described in Scheme 5.1. Compound T may be converted toan invention compound by a Suzuki coupling with a boronic acid, althoughother coupling conditions commonly known to the skilled practitioner mayalso be used. This route is particularly useful for compounds containinga biaryl A-B group. In situations where a tert-butylsulphonamide ispresent in B, which occurs in some of the particularly preferredcompounds, the sulphonamide may be formed by stirring withtrifluoroacetic acid for 16 h.

Another approach to the preparation of invention compounds whereinX^(II) in

(c.f., Formulas II-X), is N and

is a bond is provided in Scheme 5.3. The synthetic routes commences withformation of acrylamide U as disclosed in Scheme 5.1. A diazoacetatesuch as ethyl diazoacetate is then mixed with acrylamide U to afford theappropriately substituted dihydropyrazole V. Similar chemistry to thatdescribed in Scheme 5.1 allows conversion of V to W. Reduction of theester moietry in W is then achieved using a reducing agent such assuper-hydride to afford the hydroxyl containing invention compound X.

Alternatively, invention compounds wherein X^(II) in

(c.f., Formulas II-X), is N and “- - - -” is a bond is provided inScheme 5.4. Here, the acrylic ester Y is reacted with a diazocompound toform the dihydropyrazole Z. Addition of a chloroformate affordscompounds of formula AA. Deprotection of the ester is achieved by acid,such as TFA or hydrogen chloride to afford compounds of formula BB.Addition of an aniline with a coupling reagent such as EEDQ and baseaffords compounds of formula CC. Deprotection of the carbamate with Pd/Cand hydrogen affords compounds of formula DD which may then be reactedwith isocyanates to afford invention compounds of formula FF.

Other methods for making compounds of the invention or variations of theabove Schemes are provided in the Examples section.

Not all compounds of of the invention falling into a given class may becompatible with some of the reaction conditions described. Suchrestrictions are readily apparent to those skilled in the art of organicsynthesis, and alternative methods must then be used.

Some of the compounds of Formula I are capable of further formingpharmaceutically acceptable acid-addition and/or base salts. All ofthese forms are within the scope of the present invention. Thus,pharmaceutically acceptable acid addition salts of the compounds ofFormula I include salts derived from nontoxic inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,hydrofluoric, phosphorous, and the like, as well as the salts derivedfrom nontoxic organic acids, such as aliphatic mono- and dicarboxylicacids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids,alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonicacids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate,sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, acetate,trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate,succinates suberate, sebacate, fumarate, maleate, mandelate, benzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate,benzensoulfonate, toluenesulfonate, phenylacetate, citrate, lactate,maleate, tartrate, methanesulfonate, and the like. Also contemplated aresalts of amino acids such as arginate and the like and gluconate,galacturonate (see, for example, Berge S. M. et al., “PharmaceuticalSalts,” Journal of Pharmaceutical Science, 1977;66:1-19).

The acid addition salt of said basic compounds are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner.

Pharmaceutically acceptable base addition salts are formed with metalsor amines, such as alkali and alkaline earth metals or organic amines.Examples of metals used as cations are sodium, potassium, magnesium,calcium, and the like. Examples of suitable amines areN,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine(see, for example, Berge S. M., supra., 1977).

The base addition salts of said acidic compounds are prepared bycontacting the free acid form with a sufficient amount of the desiredbase to produce the salt in the conventional manner.

Examples of pharmaceutically acceptable, non-toxic esters of thecompounds of this invention include C₁-C₆ alkyl esters wherein the alkylgroup is a straight or branched chain. Acceptable esters also includeC₅-C₇ cycloalkyl esters as well as arylalkyl esters such as, but notlimited to benzyl. C₁-C₄ alkyl esters are preferred. Esters of thecompounds of the present invention may be prepared according toconventional methods.

Examples of pharmaceutically acceptable, non-toxic amides of thecompounds of this invention include amides derived from ammonia, primaryC₁-C₆ alkyl amines and secondary C₁-C₆ dialkyl amines wherein the alkylgroups are straight or branched chain. In the case of secondary amines,the amine may also be in the form of a 5- or 6-membered heterocyclecontaining one nitrogen atom. Amides derived from ammonia, C₁-C₃ alkylprimary amines and C₁-C₂ dialkyl secondary amines are preferred. Amidesof the compounds of the invention may be prepared according toconventional methods.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

Certain of the compounds of the present invention possess one or morechiral centers and each center may exist in the R(D) or S(L)configuration. The present invention includes all enantiomeric andepimeric forms, as well as the appropriate mixtures thereof.

The compounds of Formula I can be formulated as pharmaceuticalcompositions and administered to a mammalian host, such as a humanpatient in a variety of forms adapted to the chosen route ofadministration, i.e., orally or parenterally, by intravenous,intramuscular, topical or subcutaneous routes.

Thus, the present compounds may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptable vehicle suchas an inert diluent or an assimilable edible carrier. They may beenclosed in hard or soft shell gelatin capsules, may be compressed intotablets, or may be incorporated directly with the food of the patient'sdiet. For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparations shouldcontain at least 0.1% of active compound. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2 to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level will beobtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form must be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, the preferred methods of preparationare vacuum drying and the freeze drying techniques, which yield a powderof the active ingredient plus any additional desired ingredient presentin the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orFormulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings, or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Examples of useful dermatological compositions which can be used todeliver the compounds of Formula I to the skin are known to the art; forexample, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat.No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman(U.S. Pat. No. 4,820,508).

Useful dosages of the compounds of Formula I can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949.

Generally, the concentration of the compound(s) of Formula I in a liquidcomposition, such as a lotion, will be from about 0. 1-25 wt-%,preferably from about 0.5-10 wt-%. The concentration in a semi-solid orsolid composition such as a gel or a powder will be about 0.1-5 wt-%,preferably about 0.5-2.5 wt-%.

The amount of the compound, or an active salt or derivative thereof,required for use in treatment will vary not only with the particularsalt selected but also with the route of administration, the nature ofthe condition being treated and the age and condition of the patient andwill be ultimately at the discretion of the attendant physician orclinician.

The compounds of the present invention can be administered to a patientat dosage levels in the range of about 0.1 to about 2,000 mg per day.For a normal human adult having a body weight of about 70 kilograms, adosage in the range of about 0.01 to about 10 mg per kilogram of bodyweight per day is preferable. However, the specific dosage used canvary. For example, the dosage can depended on a numbers of factorsincluding the requirements of the patient, the severity of the conditionbeing treated, and the pharmacological activity of the compound beingused. The determination of optimum dosages for a particular patient iswell-known to those skilled in the art.

Ideally, the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from about 0.5 to about75 μM, preferably, about 1 to 50 μM, most preferably, about 0. 1 toabout 5 μM. This may be achieved, for example, by the intravenousinjection of a 0.05 to 5% solution of the active ingredient, optionallyin saline, or orally administered as a bolus containing about 10-500 mgof the active ingredient. Desirable blood levels may be maintained bymultiple oral dosing, or continuous infusion to provide about 0.01-5.0mg/kg/hr or by intermittent infusions containing about 0.4-15 mg/kg ofthe active ingredient(s).

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

The following examples illustrate the various embodiments of the presentinvention. Those skilled in the art will recognize many variations thatare within the spirit of the present invention and scope of the claims.

Biological Assays

The invention compounds have demonstrated factor Xa inhibitory activityin the standard assays commonly employed by those skilled in the art.

A. Determination of Factor Xa IC₅₀

The ability of compounds to act as inhibitors of human factor Xacatalytic activity is assessed by determination of that concentration oftest substance that inhibits by 50% (IC₅₀) the ability of human factorXa to cleave the chromogenic substrate S2765(N—CBz-D-Arg-L-Gly-L-Arg-p-nitroanilide. 2HCl, DiaPharma). The IC₅₀ wasdetermined at 3 μM and 30 pM concentrations human factor Xa (EnzymeResearch Laboratories). These concentrations were achieved by diluting a21.087 μM stock solution of factor Xa in the appropriate amount of abuffer comprising 10 μM HEPES, 150 μM NaCl, 0.1% BSA, pH 7.4 (HBSAbuffer). Accordingly, 5 μL of the compound to be tested in DMSO (2%final) is added to the factor Xa/buffer solution and incubated for 60minutes at room temperature.

The IC₅₀ is determined by monitoring the increase in absorbance at 390nm exicitation, 460 nm emission, with a 455 nm cutoff, in a fluorometricplate reader. Results of the IC₅₀ at 3 pM and 30 pM enzymeconcentrations are provided in Table 1. TABLE 1 FXA 3 pM IC₅₀ FXA 30 pMEXAMPLE (mM) IC₅₀ (mM) (R)-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro- 0.0199 0.0270 phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4- yl)-amide]Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- 0.0355 amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)- amide]Pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro-pyridin- 0.25682-yl)-amide] 2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)- amide]Pyrrolidine-1,2-dicarboxylic acid 1-[(2,4-difluoro- 9.1175phenyl)-amide] 2-[(3-fluoro-2′-sulfamoyl-biphenyl-4- yl)-amide]Pyrrolidine-1,2-dicarboxylic acid 2-[(3-fluoro-2′- 0.3890sulfamoyl-biphenyl-4-yl)-amide] 1-p-tolylamidePyrrolidine-1,2-dicarboxylic acid 2-[(3-fluoro-2′- 0.8730sulfamoyl-biphenyl-4-yl)-amide] 1-[(4-methoxy- phenyl)-amide]Pyrrolidine-1,2-dicarboxylic acid 1-[(4-bromo-phenyl)- 0.0333 amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)- amide]Pyrrolidine-1,2-dicarboxylic acid 2-[(3-fluoro-2′- 0.9510sulfamoyl-biphenyl-4-yl)-amide] 1-phenylamidePyrrolidine-1,2-dicarboxylic acid 1-[(3,4-difluoro- 0.6460phenyl)-amide] 2-[(3-fluoro-2′-sulfamoyl-biphenyl-4- yl)-amide]Pyrrolidine-1,2-dicarboxylic acid 1-[(3-fluoro-4- 0.5150methyl-phenyl)-amide] 2-[(3-fluoro-2′-sulfamoyl- biphenyl-4-yl)-amide]Pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro-pyridin- 0.08042-yl)-amide] 2-[(3-fluoro-2′-methanesulfonyl-biphenyl- 4-yl)-amide]Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- 0.0172 amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)- amide]Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- 0.0730 amide]2-{[5-(2-sulfamoyl-phenyl)-pyridin-2-yl]- amide}Pyrrolidine-1,2-dicarboxylic acid 2-[(3-chloro-2′- 0.1010methanesulfonyl-biphenyl-4-yl)-amide] 1-[(5-chloro- pyridin-2-yl)-amide]Pyrrolidine-1,2-dicarboxylic acid 2-[(3-chloro-2′- 0.0166methanesulfonyl-biphenyl-4-yl)-amide] 1-[(4-chloro- phenyl)-amide]Pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro-pyridin- 0.27702-yl)-amide] 2-{[5-(2-sulfamoyl-phenyl)-pyridin-2-yl]- amide}(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.00071-[(4-chloro-phenyl)-amide] 2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide] Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)- 0.1560 amide]2-{[4-(1-methyl-4,5-dihydro-1H-imidazol-2- yl)-phenyl]-amide}Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- 0.0273 amide]2-[(2′-methanesulfonyl-biphenyl-4-yl)-amide]Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- 0.0591 amide]2-[(2′-methanesulfonyl-3-methyl-biphenyl-4- yl)-amide](2R,4R)-4-methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0003748331-[(4-chloro-phenyl)-amide] 2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide](2R)-4-oxo-pyrrolidine-1,2-dicarboxylic acid 1-[(4- 0.007596667chloro-phenyl)-amide] 2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide](2R,4S)-4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1- 0.004443333[(4-chloro-phenyl)-amide]-2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide](2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.010652-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide] 1-p-tolylamide(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.00285752-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]1-[(4-fluoro-phenyl)-amide](2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.00711251-[(5-chloro-pyridin-2-yl)-amide] 2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide] Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)- 0.0806 amide]2-[(2′-methanesulfonyl-3-trifluoromethyl- biphenyl-4-yl)-amide](2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.00141-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide] 2-{[4-(2-oxo-piperidin-1- yl)-phenyl]-amide}(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.00251-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.00411-[(5-chloro-pyridin-2-yl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.01491-[(5-chloro-pyridin-2-yl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1- 0.0084[(5-chloro-pyridin-2-yl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1- 0.0045[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}(2R,4R)-4-Propoxy-pyrrolidine-1,2-dicarboxylic acid 0.00081-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}(2R,4R)-4-Propoxy-pyrrolidine-1,2-dicarboxylic acid 0.00201-[(5-chloro-pyridin-2-yl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}(2R,4R)-4-Cyano-pyrrolidine-1,2-dicarboxylic acid 1- 0.0050[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}(2R,4R)-4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1- 0.0510[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.01101-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-azetidin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.12231-[(5-chloro-pyridin-2-yl)-amide] 2-{[2-fluoro-4-(2-oxo-azetidin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 54% at 1 uM1-[(5-chloro-pyridin-2-yl)-amide] 2-{[2-fluoro-4-(2-oxo-azetidin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.00401-[(5-chloro-pyridin-2-yl)-amide] 2-{[2-fluoro-4-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.02941-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-azepan-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.00411-[(5-chloro-pyridin-2-yl)-amide] 2-{[2-fluoro-4-(2-oxo-azepan-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.03001-[(5-chloro-pyridin-2-yl)-amide] 2-{[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.00131-[(4-chloro-phenyl)-amide] 2-{[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide} (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1- 0.0004 [(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1- TBD[(5-chloro-pyridin-2-yl)-amide] 2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid TBD1-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-hydroxymethyl-5-oxo-pyrrolidin-1-yl)-phenyl]-amide}(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.25601-[(4-chloro-phenyl)-amide] 2-{[4-(2,3-dimethyl-5-oxo-2,5-dihydro-pyrazol-1-yl)-phenyl]-amide}4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4- 0.0110chloro-phenyl)-amide] 2-{[4-(2-hydroxymethyl-pyrrolidin-1-yl)-phenyl]-amide}(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.06401-[(4-chloro-phenyl)-amide] 2-[(4-pyrrolidin-1-yl- phenyl)-amide](2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.03441-[(4-chloro-phenyl)-amide] 2-[(4-pyrazol-1-yl- phenyl)-amide](2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.04341-[(4-chloro-phenyl)-amide] 2-[(2-fluoro-4-pyrazol-1- yl-phenyl)-amide](2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.06191-[(4-chloro-phenyl)-amide] 2-[(4-[1,2,4]triazol-1-yl- phenl)-amide](2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.19031-[(4-chloro-phenyl)-amide] 2-[(4-[1,2,3]triazol-2-yl- phenyl)-amide](2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 26% at 1 uM1-[(4-chloro-phenyl)-amide] 2-[(4-[1,2,3]triazol-1-yl- phenyl)-amide](2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.07932-[(4-acetylamino-phenyl)-amide] 1-[(4-chloro- phenyl)-amide](2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 36% at 1 uM1-[(4-chloro-phenyl)-amide] 2-{[4-(cyclopentanecarbonyl-amino)-phenyl]-amide}4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4- 32% at 1 uMchloro-phenyl)-amide] 2-[(4-pyrimidin-5-yl-phenyl)- amide](2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0410001-[(4-chloro-phenyl)-amide] 2-[(4-pyrazol-1-yl- phenyl)-amide](2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0320001-[(4-chloro-phenyl)-amide] 2-[(2-fluoro-4-pyrazol-1- yl-phenyl)-amide](2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1- 0.029000[(4-chloro-phenyl)-amide] 2-[(2-fluoro-4-pyrazol-1-yl- phenyl)-amide](2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1- 0.018000[(4-chloro-phenyl)-amide] 2-[(4-pyrazol-1-yl-phenyl)- amide](2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0820001-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(3-methyl-pyrazol-1-yl)-phenyl]-amide}(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.0210001-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(5-methyl-pyrazol-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0096001-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(5-methyl-pyrazol-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0150001-[(4-chloro-phenyl)-amide] 2-{[4-(5-methyl-pyrazol-1-yl)-phenyl]-amide} (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid0.049000 1-[(4-chloro-phenyl)-amide] 2-{[4-(3,5-dimethyl-pyrazol-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0200001-[(4-chloro-phenyl)-amide] 2-{[4-(3,5-dimethyl-pyrazol-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0100001-[(4-chloro-phenyl)-amide] 2-{[4-(3,5-dimethyl-pyrazol-1-yl)-2-fluoro-phenyl]-amide}(2R,4S)-4-Amino-pyrrolidine-1,2-dicarboxylic acid 1- 0.010000[(4-chloro-phenyl)-amide] 2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide](2R,4R)-4-Amino-pyrrolidine-1,2-dicarboxylic acid 1- 0.025925[(4-chloro-phenyl)-amide] 2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide](2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.0007701-[(4-chloro-phenyl)-amide] 2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide] (2R)-4-Hydroxyimino-pyrrolidine-1,2-dicarboxylic0.002108 acid 1-[(4-chloro-phenyl)-amide] 2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide](2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.0019221-[(4-chloro-phenyl)-amide] 2-[(3-fluoro-2′-methylsulfamoyl-biphenyl-4-yl)-amide](2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.0011881-[(4-chloro-phenyl)-amide] 2-[(2′-dimethylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide](2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0010211-[(5-chloro-pyridin-2-yl)-amide] 2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide](2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0004911-[(4-chloro-phenyl)-amide] 2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide] (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1- 0.000701 [(5-chloro-pyridin-2-yl)-amide] 2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide](2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1- 0.000276[(4-chloro-phenyl)-amide] 2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide] (2R,4S)-4-Methoxy-pyrrolidine-1,2-dicarboxylicacid 0.001685 1-[(4-chloro-phenyl)-amide] 2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide](2R,4R)-4-Fluoro-pyrrolidine-1,2-dicarboxylic acid 1- 0.001200[(4-chloro-phenyl)-amide] 2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide](2R)-4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid 1- 0.005360[(4-chloro-phenyl)-amide] 2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide](2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0018732-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]1-[(4-fluoro-phenyl)-amide](2R,4R)-4-Acetylamino-pyrrolidine-1,2-dicarboxylic 0.010545 acid1-[(4-chloro-phenyl)-amide] 2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide](2R,4R)-4-Methanesulfonylamino-pyrrolidine-1,2- 0.001735 dicarboxylicacid 1-[(4-chloro-phenyl)-amide] 2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide](2R,4S)-4-(1H-Tetrazol-5-yl)-pyrrolidine-1,2- 0.038850 dicarboxylic acid1-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}(2R,4S)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0117701-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0062101-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-methyl-imidazol-1-yl)-phenyl]-amide}(2R,4R)-4-Cyano-pyrrolidine-1,2-dicarboxylic acid 1- 0.055475[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}(2R,4R)-4-(1H-Tetrazol-5-yl)-pyrrolidine-1,2- 0.007973 dicarboxylic acid1-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}(2R,4R)-4-Trifluoromethyl-pyrrolidine-1,2- 0.032950 dicarboxylic acid1-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0019501-[(4-chloro-phenyl)-amide] 2-[(2′-cyano-3-fluoro- biphenyl-4-yl)-amide](2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0016332-[(2′-aminomethyl-3-fluoro-biphenyl-4-yl)-amide] 1-[(4-chloro-phenyl)-amide] (2R,4R)-4′-{[1-(4-Chloro-phenylcarbamoyl)-4-0.007112 methoxy-pyrrolidine-2-carbonyl]-amino}-3′-fluoro-biphenyl-2-carboxylic acid methyl ester(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.000291-[(4-chloro-phenyl)-amide] 2-{[4-(2,5-dihydro-pyrrole-1-carbonyl)-phenyl]-amide}(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.0151-[(4-chloro-phenyl)-amide] 2-[(4-dimethylcarbamoyl-2-fluoro-phenyl)-amide] (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylicacid 0.0081 1-[(4-chloro-phenyl)-amide] 2-{[4-(pyrrolidine-1-carbonyl)-phenyl]-amide} Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)- 0.081 amide]2-{[4-(pyrrolidine-1-carbonyl)-phenyl]-amide}(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.0241-[(4-chloro-phenyl)-amide] 2-{[4-(2-methyl-pyrrolidine-1-carbonyl)-phenyl]-amide}(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.0371-[(4-chloro-phenyl)-amide] 2-{[4-(ethyl-methyl-carbamoyl)-phenyl]-amide} (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylicacid 0.010 1-[(4-chloro-phenyl)-amide] 2-[(4-dimethylcarbamoyl-phenyl)-amide] (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.0111-[(4-chloro-phenyl)-amide] 2-{[4-(2R-methyl-pyrrolidine-1-carbonyl)-phenyl]-amide}(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.0821-[(4-chloro-phenyl)-amide] 2-{[4-(2S-methyl-pyrrolidine-1-carbonyl)-phenyl]-amide}(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.00961-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(pyrrolidine-1-carbonyl)-phenyl]-amide}(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.0351-[(4-chloro-phenyl)-amide] 2-{[4-(pyrrolidine-1-carbonyl)-2-pyrrolidin-1-yl-phenyl]-amide}(2R,4R)-4-{[1-(4-Chloro-phenylcarbamoyl)-4- 0.020hydroxy-pyrrolidine-2-carbonyl]-amino}-3-pyrrolidin- 1-yl-benzoic acidmethyl ester (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.0612-{[4-(azetidine-1-carbonyl)-phenyl]-amide} 1-[(4- chloro-phenyl)-amide](2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.0841-[(5-chloro-pyridin-2-yl)-amide] 2-{[2-fluoro-4-(pyrrolidine-1-carbonyl)-phenyl]-amide}(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.0811-[(5-chloro-pyridin-2-yl)-amide] 2-{[4-(pyrrolidine-1-carbonyl)-phenyl]-amide} (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylicacid 0.044 1-[(5-chloro-pyridin-2-yl)-amide] 2-[(4-dimethylcarbamoyl-phenyl)-amide](2R,4R)-4-{[1-(4-Chloro-phenylcarbamoyl)-4- 0.029hydroxy-pyrrolidine-2-carbonyl]-amino}-3- dimethylamino-benzoic acidmethyl ester (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.00731-[(4-chloro-phenyl)-amide] 2-{[4-(pyrrolidine-1-carbonyl)-phenyl]-amide} (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylicacid 0.0049 1-[(4-chloro-phenyl)-amide] 2-[(4-dimethylcarbamoyl-phenyl)-amide] (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1-0.0057 [(4-chloro-phenyl)-amide] 2-{[4-(pyrrolidine-1-carbonyl)-phenyl]-amide} (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylicacid 1- 0.0039 [(4-chloro-phenyl)-amide] 2-[(4-dimethylcarbamoyl-phenyl)-amide] (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid0.0062 1-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(pyrrolidine-1-carbonyl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.00611-[(4-chloro-phenyl)-amide] 2-[(4-dimethylcarbamoyl-2-fluoro-phenyl)-amide] (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylicacid 1- 0.0044 [(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(pyrrolidine-1-carbonyl)-phenyl]-amide} (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylicacid 1- 0.0029 [(4-chloro-phenyl)-amide] 2-[(4-dimethylcarbamoyl-2-fluoro-phenyl)-amide] (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylicacid 0.0052 1-[(4-chloro-phenyl)-amide] 2-{[2-methyl-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}(2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1- 0.0020[(4-chloro-phenyl)-amide] 2-{[2-methyl-4-(2-oxo-piperidin-1-yl)-phenyl]-amide} Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)- 0.066 amide]2-[(2-fluoro-4-quinolin-8-yl-phenyl)-amide] Pyrrolidine-1,2-dicarboxylicacid 1-[(4-chloro-phenyl)- 0.0098 amide]2-[(3,5-difluoro-2′-methanesulfonyl-biphenyl-4- yl)-amide]Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- 0.018 amide]2-[(2′-methanesulfonyl-2-methyl-biphenyl-4- yl)-amide](2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.000731-[(4-chloro-phenyl)-amide] 2-[(2′-methanesulfonyl-biphenyl-4-yl)-amide] (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylicacid 0.0039 1-[(4-chloro-phenyl)-amide] 2-[(2′-methanesulfinyl-biphenyl-4-yl)-amide] (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylicacid 0.053 1-[(4-chloro-phenyl)-amide] 2-[(3-methyl-2′-methylsulfanyl-biphenyl-4-yl)-amide](2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.00121-[(4-chloro-phenyl)-amide] 2-[(2-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide](2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.000681-[(4-chloro-phenyl)-amide] 2-[(2′-methanesulfonyl-3-methyl-biphenyl-4-yl)-amide](2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.00151-[(4-chloro-phenyl)-amide] 2-[(2′-methanesulfonyl-3-trifluoromethyl-biphenyl-4-yl)-amide]5-Methyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid 0.0056231-[(4-chloro-phenyl)-amide] 5-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide] 3-Hydroxymethyl-4,5-dihydro-pyrazole-1,5- 0.011267dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 5-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]4,5-Dihydro-pyrazole-1,5-dicarboxylic acid 1-[(4- 0.008015chloro-phenyl)-amide] 5-[(3-fluoro-2′-sulfamoyl- biphenyl-4-yl)-amide](R) 4,5-Dihydro-pyrazole-1,5-dicarboxylic acid 1-[(4- 0.007738chloro-phenyl)-amide] 5-[(3-fluoro-2′-sulfamoyl- biphenyl-4-yl)-amide]4,5-Dihydro-pyrazole-1,5-dicarboxylic acid 1-[(4- 0.044850chloro-phenyl)-amide] 5-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide} 4,5-Dihydro-pyrazole-1,5-dicarboxylic acid 1-[(4-0.008718 chloro-phenyl)-amide] 5-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]1-(4-Chloro-phenylcarbamoyl)-5-(3-fluoro-2′- 0.040850methanesulfonyl-biphenyl-4-ylcarbamoyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.0589001-[(4-chloro-phenyl)-amide] 2-[(2′-methoxy-biphenyl- 4-yl)-amide](2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 0.0741001-[(4-chloro-phenyl)-amide] 2-[(2′-hydroxy-biphenyl- 4-yl)-amide](2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0585751-[(4-chloro-phenyl)-amide] 2-[(2-fluoro-4-iodo- phenyl)-amide](2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0004041-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0011531-[(5-chloro-pyridin-2-yl)-amide] 2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0084981-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(3-hydroxy-2-oxo-piperidin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0076651-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-tetrahydro-pyrimidin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0364251-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-imidazolidin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0455251-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(2-oxo-oxazolidin-3-yl)-phenyl]-amide}(2R,4R)-1-(4-{[1-(4-Chloro-phenylcarbamoyl)-4- 0.011000methoxy-pyrrolidine-2-carbonyl]-amino}-3-fluoro-phenyl)-2-oxo-piperidine-3-carboxylic acid ethyl ester(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0008621-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(3-methoxy-2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0050751-[(5-chloro-pyridin-2-yl)-amide] 2-{[2-fluoro-4-(3-methoxy-2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0003831-[(4-chloro-phenyl)-amide] 2-{[4-(3-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0017931-[(5-chloro-pyridin-2-yl)-amide] 2-{[4-(3-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0430501-[(4-chloro-phenyl)-amide] 2-[(4-morpholin-4-yl- phenyl)-amide](2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0023031-[(4-chloro-phenyl)-amide] 2-{[4-(2-methyl-5-oxo-pyrrolidin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0119751-[(5-chloro-pyridin-2-yl)-amide] 2-{[4-(2-methyl-5-oxo-pyrrolidin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0027571-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(4-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0121001-[(5-chloro-pyridin-2-yl)-amide] 2-{[2-fluoro-4-(4-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0007431-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(5-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0035001-[(5-chloro-pyridin-2-yl)-amide] 2-{[2-fluoro-4-(5-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0021701-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(4-methoxy-2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0049671-[(5-chloro-pyridin-2-yl)-amide] 2-{[2-fluoro-4-(4-methoxy-2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid TBD1-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(3-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid TBD1-[(5-chloro-pyridin-2-yl)-amide] 2-{[2-fluoro-4-(3-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 0.0012101-[(4-chloro-phenyl)-amide] 2-{[2-fluoro-4-(6-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]-amide}(2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid TBD2-{[4-(5-chloro-2-oxo-2H-pyridin-1-yl)-2-fluoro- phenyl]-amide}1-[(4-chloro-phenyl)-amide] 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid2-[(4-tert- 0.0260 butyl-phenyl)-amide] 1-[(4-chloro-phenyl)-amide]4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4- 0.0006chloro-phenyl)-amide] 2[(3,5′difluoro-2′-sulfamoyl-biphenyl-4-yl)-amide] 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4-0.0650 chloro-phenyl)-amide] 2-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amide]4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4- 0.0070chloro-phenyl)-amide] 2-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl)-amide]4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5- 0.0580chloro-pyridin-2-yl)-amide] 2-{[4-(2,3-dimethyl-5-oxo-2,5-dihydro-pyrazol-1-yl)-phenyl]-amide}4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4- 0.0800chloro-phenyl)-amide] 2-{[4-(2,3-dimethyl-5-oxo-2,5-dihydro-pyrazol-1-yl)-phenyl]-amide}4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4- 0.0050chloro-phenyl)-amide] 2-[(2-oxo-2H-[1,3′]bipyridinyl- 6′-yl)-amide]4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(5- 0.0900chloro-pyridin-2-yl)-amide] 2-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl)-amide]-TFA Salt4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4- 0.0170chloro-phenyl)-amide] 2-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl)-amide] 4-Ethoxy-pyrrolidine-1,2-dicarboxylicacid 1-[(4- 0.0030 chloro-phenyl)-amide] 2-[(2-oxo-2H-[1,3′]bipyridinyl-6′-yl)-amide] 4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-[(4- 0.0420chloro-phenyl)-amide] 2-{[2-fluoro-4-(6-oxo-6H-pyridazin-1-yl)-phenyl]-amide}

Similarly, Table 2 provides the percent inhibition at 3 pM concentrationof factor Xa and compound concentrations of 4 μM and 1 μM. TABLE 2 Fxa3PM Fxa 3PM Name % Inhibition at 4 uM % Inhibition at 1 uMPyrrolidine-1,2-dicarboxylic acid 2-[(3-fluoro-2′-sulfamoyl- 19.22biphenyl-4-yl)-amide] 1-[(4-isopropyl-phenyl)-amide]Pyrrolidine-1,2-dicarboxylic acid 2-[(3-fluoro-2′-sulfamoyl- 25.1biphenyl-4-yl)-amide] 1-[(4-trifluoromethyl-phenyl)-amide]Pyrrolidine-1,2-dicarboxylic acid 2-[(3-fluoro-2′-sulfamoyl- 36.21biphenyl-4-yl)-amide] 1-[(3-methoxy-phenyl)-amide]Pyrrolidine-1,2-dicarboxylic acid 1-[(4-ethyl-phenyl)-amide] 38.142-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]Pyrrolidine-1,2-dicarboxylic acid 1-[(3-acetyl-phenyl)-amide] 21.042-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]Pyrrolidine-1,2-dicarboxylic acid 1-[(5-chloro-2-methyl- 19.84phenyl)-amide] 2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)- amide]Pyrrolidine-1,2-dicarboxylic acid 1-[(2-fluoro-phenyl)-amide] 37.212-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]Pyrrolidine-1,2-dicarboxylic acid 1-[(3-chloro-4-fluoro- 41.07phenyl)-amide] 2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)- amide]Pyrrolidine-1,2-dicarboxylic acid 1-[(3-chloro-phenyl)-amide] 55.972-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]Pyrrolidine-1,2-dicarboxylic acid 1-[(4-cyano-phenyl)-amide] 51.862-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-2-methyl- 38.88phenyl)-amide] 2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)- amide]Pyrrolidine-1,2-dicarboxylic acid 1-[(3,4-dichloro-phenyl)- 41.71 amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]Pyrrolidine-1,2-dicarboxylic acid 2-[(3-fluoro-2′-sulfamoyl- 21.61biphenyl-4-yl)-amide] 1-[(3-trifluoromethyl-phenyl)-amide]Pyrrolidine-1,2-dicarboxylic acid 1-[(4-dimethylamino- 19.93phenyl)-amide] 2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)- amide](2S)-Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)- 46.5 amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]Pyrrolidine-1,2-dicarboxylic acid 1-[(4-chloro-phenyl)-amide] 16.582-[(4-cyano-phenyl)-amide] Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide] 36.642-{[4-(1H-tetrazol-5-yl)-phenyl]-amide}

The foregoing biological tests establish that the compounds of thepresent invention are potent inhibitors of the Faxtor Xa. Accordingly,the compounds of the present invention are useful in pharmaceuticalformulations for preventing and treating thrombotic disorders. Suchdisorders include venous thrombosis, deep vein thrombosis,thrombophlebitis, arterialembolism, coronary and cerebral arterialthrombosis, cerebral embolism, kidney embolism, pulmonary embolism,first or recurrent myocardial infarction, unstable angina, cerebralinfarction, stroke, and atherosclerosis.

To further assist in understanding the present invention, the followingnon-limiting examples of such factor Xa inhibitory compounds areprovided. The following examples, of course, should not be construed asspecifically limiting the present invention, variations presently knownor later developed, which would be within the purview of one skilled inthe art and considered to fall within the scope of the present inventionas described herein. Preferred synthetic routes for intermediatesinvolved in the synthesis as well as the resulting anti-thromboticcompounds of the present invention follow.

EXAMPLE 1 (R)-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]

Step 1:(R)-2-(4-Bromo-2-fluoro-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid9H-fluoren-9-ylmethyl ester

Fmoc-D-Pro (1.2 g, 3.56 mmol) was suspended in 10 mL dry dichloromethane(DCM), cooled in an ice water bath, and then thionyl chloride (0.78 mL,10.7 mmol) was added slowly. After addition was complete, the ice waterbath was removed and the reaction was stirred at ambient temperatureovernight. The solution was concentrated to dryness. The oil wasredissolved in 20 mL dry DCM under an Ar atmosphere, and4-bromo-2-fluoroaniline (0.81 g, 4.3 mmol) was added, followed by drypyridine (0.87 mL, 10.7 mmol). The mixture was stirred at ambienttemperature for 4 hours, then concentrated. The residue was redissolvedin 100 mL EtOAc, washed with 1M HCl (3×50 mL), brine (2×50 mL), driedwith MgSO₄, filtered and concentrated to yield the title product as asticky oil. (1.8 g, 99%) APCI (AP+): 509.2, 511.2 (M+H)⁺.

Step 2: (R)-Pyrrolidine-2-carboxylic acid(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide

(R)-2-(4-Bromo-2-fluoro-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid9H-fluoren-9-ylmethyl ester (1.78 g, 3.49 mmol),2-(N-tert-butyl)phenylsulfonamide boronic acid (1.35 g, 5.24 mmol), andtetrabutylammonium bromide (60 mg, 0. 17 mmol) were combined in 40 mLtoluene. 3.5 mL of an aqueous 2M sodium carbonate solution was thenadded, followed by tetrakistriphenylphosphine palladium(0) (200 mg, 0.17mmol). The resulting solution was heated at reflux overnight, and cooledto room temperature, partitioned between EtOAc (250 mL) and water (150mL). The combined organic layers were washed with water (2×100 mL),brine, dried with MgSO₄, filtered and concentrated. Purification bycolumn chromatography on silica gel eluting with 10% EtOAc in hexanes,then EtOAc, and then to MeOH/NH₄OH/EtOAc (5:1:94) provided the titlecompound as an oil. (1.03 g, 70%) APCI (AP+): 420.3 (M+H)⁺.

Step 3: (R)-pyrrolidine-1,2-dicarboxylic acid2-[(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide]1-[(4-chloro-phenyl)-amide]

(R)-Pyrrolidine-2-carboxylic acid(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide (0.25 g, 0.6 mmol)and 4-chlorophenylisocyanate (90 mg, 0.6 mmol) were combined in 10 mLDCM and stirred at ambient temperature for one hour. The solution wasconcentrated. The residue was purified on a silica gel column elutingwith 50% EtOAc in hexanes to provide the title compound as a white foam.(0.225 g, 66%) APCI (AP−): 571.3, 573.3 (M−H)⁻.

Step 4: (R)-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]

(R)-pyrrolidine-1,2-dicarboxylic acid2-[(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide]1-[(4-chloro-phenyl)-amide](0.22 g, 0.38 mmol) was stirred in 20 mL trifluoroacetic acid at ambienttemperature overnight. The solution was concentrated, then purified on asilica gel column eluting with 50% EtOAc in hexanes, then 75% EtOAc inhexanes. The pure fractions were combined and concentrated, thenredissolved in acetonitrile/water and lyophilized to yield titlecompound as a white solid. (0.15 g, 76%) APCI (AP−): 515.2, 517.2(M−H)⁻.

EXAMPLE 2 Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]

Step 1: Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester

DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H₂O (2:1),and 87 mL of a 2M NaOH solution was added, followed by Boc₂O (24.6 g,113 mmol). The reaction mixture was stirred at ambient temperatureovernight. The THF was removed in vacuo. The remaining aqueous mixturewas acidified to pH 3 with aqueous citric acid, extracted twice withEtOAc. The combined organinc layers were washed with water, brine, driedwith MgSO₄, filtered and concentrated to yield the title compound as awhite solid. (18.7 g, quant.) APCI (AP−): 214.1 (M−H)⁻.

Step 2:2-(2′-tert-Butylsulfamoyl-3-fluoro-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.6 g, 7.4 mmol)was dissolved in 40 mL dry diethyl ether under Ar. The solution wascooled in an ice water bath as dry pyridine (3 mL, 37.2 mmol) was added,followed by the dropwise addition of oxalyl chloride (1.6 mL, 18.6mmol). A precipitate formed immediately. The reaction was stirredvigorously at 0° C. for one hour, then at ambient temperature for onehour. 50 mL diethyl ether were added, and the mixture was filtered. Thefiltered off solids were washed with diethyl ether. The filtrates werecombined and concentrated to give an off-white oil. The oil wasredissolved in 40 mL dry DCM under Ar, cooled to 0° C., and 3 mL ofpyridine were added, followed by 4′-amino-3′-fluoro-biphenyl-2-sulfonicacid tert-butylamide (2 g, 6.2 mmol). The reaction was allowed to warmto ambient temperature, stirred for 3 hours then concentrated. Theconcentrate was redissolved in 250 mL EtOAc, washed with 10% citric acid(2×100 mL), water (3×100 mL), brine (100 mL), dried with MgSO₄, filteredand concentrated. The concentrate was purified on a silica gel columneluted with 30% moving to 50% EtOAc in hexanes. Combined andconcentrated pure fractions to yield title compound as a white solid.(1.4 g, 42%) APCI (AP−): 518.2 (M−H)⁻.

Step 3: Pyrrolidine-2-carboxylic acid(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide

2-(2′-tert-Butylsulfamoyl-3-fluoro-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (1.3 g, 2.5 mmol) was dissolved in 40 mL DCM,cooled in an ice bath, added 10 mL trifluoroacetic acid, stirred at 0°C. for 30 minutes then at ambient temperature for one hour. Concentratedsolution, redissolved in EtOAc (150 mL), washed with saturated NaHCO₃(2×100 mL), water (100 mL), brine (100 mL), dried with MgSO₄, filteredand concentrated to yield title compound as a white solid. (1 g, 91%)APCI (AP−): 418.2 (M−H)⁻.

Step 4: Pyrrolidine-1,2-dicarboxylic acid2-[(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide]1-[(4-chloro-phenyl)-amide]

Pyrrolidine-2-carboxylic acid(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide (0.3 g, 0.72 mmol)was dissolved in 10 mL dry THF under Ar, added 4-chlorophenylisocyanate(0.11 g, 0.72 mmol) and stirred at ambient temperature for one hour.Concentrated solution to yield title compound. (0.42 g, quant.) APCI

(AP−): 571.2, 573.2 (M−H)⁻.

Step 5: Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]

Pyrrolidine-1,2-dicarboxylic acid2-[(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide]1-[(4-chloro-phenyl)-amide](0.4 g, 0.7 mmol) was stirred in 10 mL trifluoroacetic acid at ambienttemperature overnight, concentrated solution, then purified on a silicagel column eluted with 50% moving to 75% EtOAc in hexanes. Combined andconcentrated pure fractions, redissolved in acetonitrile/water andlyophilized to yield title compound as a white fluffy powder. (0.26 g,72%) APCI (AP−): 515.1, 517.2 (M−H)⁻.

EXAMPLE 3 Pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]

Step 1: Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester

DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H₂O (2:1),added 87 mL of a 2M NaOH solution followed by Boc₂O (24.6 g, 113 mmol).Stirred at ambient temperature overnight. Removed THF in vacuo,acidified water to pH 3 with citric acid, extracted twice with EtOAc,washed organics with water, brine, dried with MgSO₄, filtered andconcentrated to yield title compound as a white solid. (18.7 g, quant.)APCI (AP−): 214.1 (M−H)⁻.

Step 2:2-(2′-tert-Butylsulfamoyl-3-fluoro-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.6 g, 7.4 mmol)was dissolved in 40 mL dry diethyl ether under Ar, cooled in an icewater bath, added dry pyridine (3 mL, 37.2 mmol) followed by thedropwise addition of oxalyl chloride (1.6 mL, 18.6 mmol). A precipitateforms immediately. The reaction was stirred vigorously at 0° C. for onehour, then at ambient temperature for one hour. Added 50 mL diethylether, filtered off solids washing with diethyl ether. Concentrated thefiltrates to an off-white oil. Redissolved oil in 40 mL dry DCM underAr, cooled to 0° C., added 3 mL pyridine followed by4′-amino-3′-fluoro-biphenyl-2-sulfonic acid tert-butylamide (2 g, 6.2mmol). The reaction was allowed to warm to ambient temperature, stirredfor 3 hours then concentrated. Redissolved in 250 mL EtOAc, washed with10% citric acid (2×100 mL), water (3×100 mL), brine (100 mL), dried withMgSO₄, filtered and concentrated. Purified on a silica gel column elutedwith 30% moving to 50% EtOAc in hexanes. Combined and concentrated purefractions to yield title compound as a white solid. (1.4 g, 42%) APCI(AP−): 518.2 (M−H)⁻.

Step 3: Pyrrolidine-2-carboxylic acid(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide

2-(2′-tert-Butylsulfamoyl-3-fluoro-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (1.3 g, 2.5 mmol) was dissolved in 40 mL DCM,cooled in an ice bath, added 10 mL trifluoroacetic acid, stirred at 0°C. for 30 minutes then at ambient temperature for one hour. Concentratedsolution, redissolved in EtOAc (150 mL), washed with saturated NaHCO₃(2×100 mL), water (100 mL), brine (100 mL), dried with MgSO₄, filteredand concentrated to yield title compound as a white solid. (1 g, 91%)APCI (AP−): 418.2 (M−H)⁻.

Step 3a: (5-Chloro-pyridin-2-yl)-carbamic acid 4-nitro-phenyl ester

2-Amino-5-chloropyridine (1.05 g, 8.2 mmol) was suspended in 15 mL dryDCM under Ar, added dry pyridine (0.66 mL, 8.2 mmol), cooled to 0° C.and added 4-nitrophenol chloroformate. A white precipitate formsrapidly. Stirred at ambient temperature for 1 hour, filtered off solid,washed with water and then DCM. A white solid recovered which isconsistent with title compound. (2.1 g, 88%) ¹H-NMR (D6-DMSO)

Step 4: Pyrrolidine-1,2-dicarboxylic acid2-[(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide]1-[(5-chloro-pyridin-2-yl)-amide]

Pyrrolidine-2-carboxylic acid(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide (245 mg, 0.83mmol) and (5-Chloro-pyridin-2-yl)-carbamic acid 4-nitro-phenyl ester(0.35 g, 0.83 mmol) were combined in 10 mL dry DMF under Ar, addeddiisopropylethylamine (0.15 mL, 0.83 mmol) and heated at 80° C. for 2hours. Cooled solution, taken up in EtOAc (200 mL), washed with sat.K₂CO₃ (3×150 mL), sat. NaHCO₃ (3×150 mL), brine, dried with MgSO₄,filtered and concentrated to yield title compound as a light pink solid.(0.45 g, 94%) APCI (AP−): 572.3, 574.3 (M−H)⁻.

Step 5: Pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]

Pyrrolidine-1,2-dicarboxylic acid2-[(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide]1-[(5-chloro-pyridin-2-yl)-amide](0.45 g, 0.78 mmol) was stirred in 10 mL trifluoroacetic acid at ambienttemperature for 4 hours. Reaction is sluggish. Heated to 80° C. for 30minutes. Cooled solution, concentrated, redissolved in 40 mL toluene andconcentrated. Purified on a silica gel column eluted with 75% EtOAc inhexanes. Combined and concentrated pure fractions, redissolved inacetonitrile/water and lyophilized to yield title compound as a whitefluffy powder. (0.277 g, 68%) APCI (AP−): 516.1, 518.1 (M−H)⁻.

EXAMPLE 4 Pyrrolidine-1,2-dicarboxylic acid1-[(2,4-difluoro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]

Step 1: Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester

DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H₂O (2:1),added 87 mL of a 2M NaOH solution followed by Boc₂O (24.6 g, 113 mmol).Stirred at ambient temperature overnight. Removed THF in vacuo,acidified water to pH 3 with citric acid, extracted twice with EtOAc,washed organics with water, brine, dried with MgSO₄, filtered andconcentrated to yield title compound as a white solid. (18.7 g, quant.)APCI (AP−): 214.1 (M−H)⁻.

Step 2:2-(2′-tert-Butylsulfamoyl-3-fluoro-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.6 g, 7.4 mmol)was dissolved in 40 mL dry diethyl ether under Ar, cooled in an icewater bath, added dry pyridine (3 mL, 37.2 mmol) followed by thedropwise addition of oxalyl chloride (1.6 mL, 18.6 mmol). A precipitateforms immediately. The reaction was stirred vigorously at 0° C. for onehour, then at ambient temperature for one hour. Added 50 mL diethylether, filtered off solids washing with diethyl ether. Concentrated thefiltrates to an off-white oil. Redissolved oil in 40 mL dry DCM underAr, cooled to 0° C., added 3 mL pyridine followed by4′-amino-3′-fluoro-biphenyl-2-sulfonic acid tert-butylamide (2 g, 6.2mmol). The reaction was allowed to warm to ambient temperature, stirredfor 3 hours then concentrated. Redissolved in 250 mL EtOAc, washed with10% citric acid (2×100 mL), water (3×100 mL), brine (100 mL), dried withMgSO₄, filtered and concentrated. Purified on a silica gel column elutedwith 30% moving to 50% EtOAc in hexanes. Combined and concentrated purefractions to yield title compound as a white solid. (1.4 g, 42%) APCI(AP−): 518.2 (M−H)⁻.

Step 3: Pyrrolidine-2-carboxylic acid(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide

2-(2′-tert-Butylsulfamoyl-3-fluoro-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (1.3 g, 2.5 mmol) was dissolved in 40 mL DCM,cooled in an ice bath, added 10 mL trifluoroacetic acid, stirred at 0°C. for 30 minutes then at ambient temperature for one hour. Concentratedsolution, redissolved in EtOAc (150 mL), washed with saturated NaHCO₃(2×100 mL), water (100 mL), brine (100 mL), dried with MgSO₄, filteredand concentrated to yield title compound as a white solid. (1 g, 91%)APCI (AP−): 418.2 (M−H)⁻.

Step 4: Pyrrolidine-1,2-dicarboxylic acid1-[(2,4-difluoro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]

To a solution of pyrrolidine-2-carboxylic acid(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide (0.12 mmol/mL, 0.3mmol ) in 2.5 mL of THF was added 2,4-difluorophenylisocyanate. Thereaction was shaken on an orbital shaker at ambient temperature for 2hours, then 50 mg of trisamine resin (2.4 mmol/g) was added and shakenfor 1 hour. Filtered off resin, washing with THF. The THF was blown downwith a stream of nitrogen. Added 2 mL of trifluoroacetic acid and thereaction was shaken at ambient temperature overnight. Thetrifluoroacetic acid was blown down with a stream of nitrogen.Redissolved in 2 mL EtOAc and loaded onto a silica gel column. Elutedcompound with 60% EtOAc in hexanes. Combined and concentrated purefractions, redissolved in acetonitrile/water and lyophilized to a whitefluffy powder. (0.13 g, 84%) APCI (AP−): 517.2 (M−H)⁻.

EXAMPLE 5 Pyrrolidine-1,2-dicarboxylic acid2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]1-p-tolylamide

Step 1: Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester

DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H₂O (2:1),added 87 mL of a 2M NaOH solution followed by Boc₂O (24.6 g, 113 mmol).Stirred at ambient temperature overnight. Removed THF in vacuo,acidified water to pH 3 with citric acid, extracted twice with EtOAc,washed organics with water, brine, dried with MgSO₄, filtered andconcentrated to yield title compound as a white solid. (18.7 g, quant.)APCI (AP−): 214.1 (M−H)⁻.

Step 2:2-(2′-tert-Butylsulfamoyl-3-fluoro-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.6 g, 7.4 mmol)was dissolved in 40 mL dry diethyl ether under Ar, cooled in an icewater bath, added dry pyridine (3 mL, 37.2 mmol) followed by thedropwise addition of oxalyl chloride (1.6 mL, 18.6 mmol). A precipitateforms immediately. The reaction was stirred vigorously at 0° C. for onehour, then at ambient temperature for one hour. Added 50 mL diethylether, filtered off solids washing with diethyl ether. Concentrated thefiltrates to an off-white oil. Redissolved oil in 40 mL dry DCM underAr, cooled to 0° C., added 3 mL pyridine followed by4′-amino-3′-fluoro-biphenyl-2-sulfonic acid tert-butylamide (2 g, 6.2mmol). The reaction was allowed to warm to ambient temperature, stirredfor 3 hours then concentrated. Redissolved in 250 mL EtOAc, washed with10% citric acid (2×100 mL), water (3×100 mL), brine (100 mL), dried withMgSO₄, filtered and concentrated. Purified on a silica gel column elutedwith 30% moving to 50% EtOAc in hexanes. Combined and concentrated purefractions to yield title compound as a white solid. (1.4 g, 42%) APCI(AP−): 518.2 (M−H)⁻.

Step 3: Pyrrolidine-2-carboxylic acid(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide

2-(2′-tert-Butylsulfamoyl-3-fluoro-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (1.3 g, 2.5 mmol) was dissolved in 40 mL DCM,cooled in an ice bath, added 10 mL trifluoroacetic acid, stirred at 0°C. for 30 minutes then at ambient temperature for one hour. Concentratedsolution, redissolved in EtOAc (150 mL), washed with saturated NaHCO₃(2×100 mL), water (100 mL), brine (100 mL), dried with MgSO₄, filteredand concentrated to yield title compound as a white solid. (1 g, 91%)APCI (AP−): 418.2 (M−H)⁻.

Step 4: Pyrrolidine-1,2-dicarboxylic acid2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]1-p-tolylamide

To a solution of pyrrolidine-2-carboxylic acid(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide (0.12 mmol/mL,0.24 mmol ) in 2 mL of THF was added p-tolylisocyanate. The reaction wasshaken on an orbital shaker at ambient temperature for 2 hours, then 50mg of trisamine resin (2.4 mmol/g) was added and shaken for 1 hour.Filtered off resin, washing with THF. The THF was blown down with astream of nitrogen. Added 2 mL of trifluoroacetic acid and the reactionwas shaken at ambient temperature overnight. The trifluoroacetic acidwas blown down with a stream of nitrogen. Loaded onto a silica gelcolumn and eluted using an automated ISCO system with gradient of40-100% EtOAc in hexanes over 40 minutes. Combined and concentrated purefractions, redissolved in acetonitrile/water and lyophilized to a whitefluffy powder. (0.084 g, 73%) APCI (AP−): 495.1 (M−H)⁻.

EXAMPLE 6 Pyrrolidine-1,2-dicarboxylic acid2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]1-[(4-methoxy-phenyl)-amide]

This compound was prepared using the same procedures as found forExample 5 with p-methoxyphenylisocyanate substituted forp-tolylisocyanate in step 4. (0.089 g, 72%) APCI (AP−): 511.1 (M−H)⁻.

EXAMPLE 7 Pyrrolidine-1,2-dicarboxylic acid1-[(4-bromo-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]

This compound was prepared using the same procedures as found forExample 5 with 4-bromophenylisocyanate substituted for p-tolylisocyanatein step 4. (0.097 g, 72%) APCI (AP−): 559.0, 561.0 (M−H)⁻.

EXAMPLE 8 Pyrrolidine-1,2-dicarboxylic acid2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]1-phenylamide

This compound was prepared using the same procedures as found forExample 5 with phenylisocyanate substituted for p-tolylisocyanate instep 4. (0.084 g, 73%) APCI (AP−): 481.1 (M−H)⁻.

EXAMPLE 9 Pyrrolidine-1,2-dicarboxylic acid1-[(3,4-difluoro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]

This compound was prepared using the same procedures as found forExample 5 with 3,4-difluorophenylisocyanate substituted forp-tolylisocyanate in step 4. (0.079 g, 63%) APCI (AP−): 517.0 (M−H)⁻.

EXAMPLE 10 Pyrrolidine-1,2-dicarboxylic acid1-[(3-fluoro-4-methyl-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]

This compound was prepared using the same procedures as found forExample 5 with 3-fluoro-4-methylphenylisocyanate substituted forp-tolylisocyanate in step 4. (0.083 g, 67%) APCI (AP−): 513.0 (M−H)⁻.

EXAMPLE 11 Pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

Step 1: Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester

DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H₂O (2:1),added 87 mL of a 2M NaOH solution followed by Boc₂O (24.6 g, 113 mmol).Stirred at ambient temperature overnight. Removed THF in vacuo,acidified water to pH 3 with citric acid, extracted twice with EtOAc,washed organics with water, brine, dried with MgSO₄, filtered andconcentrated to yield title compound as a white solid. (18.7 g, quant.)APCI (AP−): 214.1 (M−H)⁻.

Step 2: 2-(4-Bromo-2-fluoro-phenylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (3.8 g, 18 mmol)was dissolved in 150 mL dry diethyl ether under Ar, cooled in an icewater bath, added dry pyridine (8.6 mL, 106 mmol) followed by thedropwise addition of oxalyl chloride (4.6 mL, 53 mmol). A precipitateformed immediately. The reaction was stirred vigorously at 0° C. for onehour, then at ambient temperature for one hour. 100 mL diethyl ether wasthen added. The solides were filtered off and washed with diethyl ether.The filtrates were concentrated to an off-white oil. The solid wasredissolved oil in 50 mL dry DCM under Ar, cooled to 0° C., and 6 mLpyridine was added, followed by 4-bromo-2-fluoroaniline (3.4 g, 17.7mmol). The reaction was allowed to warm to ambient temperature, stirredfor 3 hours then concentrated. The concentrate was redissolved in 250 mLEtOAc, washed with 10% HCl (3×100 mL), brine (100 mL), dried with MgSO₄,filtered and concentrated. The residue was purified on a silica gelcolumn eluted with 20% moving to 40% EtOAc in hexanes to yield titlecompound as a white solid. (3.2 g, 47%) APCI (AP−): 385.1, 387.1 (M−H)⁻.

Step 3:2-(3-Fluoro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

2-(4-Bromo-2-fluoro-phenylcarbamoyl)-pyrrolidine-1-carboxylic acidtert-butyl ester (2 g, 4.8 mmol), 2-(methylthio)benzene boronic acid(0.98 g, 5.8 mmol), and tetrabutylammonium bromide (78 mg, 0.24 mmol)were combined in 30 mL toluene, added 5 mL of a 2M aqueous Na2CO3solution followed by tetrakistriphenylphosphine palladium(0) (0.28 g,0.24 mmol). The reaction was heated at reflux for 4 hours, cooled,concentrated, redissolved in EtOAc (250 mL), washed with water (3×200mL), brine (200 mL), dried with MgSO₄, filtered, and concentrated in thepresence of 4 g coarse silica. The residue was was purified by columnchromatography on silica gel eluting with 20% EtOAc in hexanes to yieldtitle compound as a yellow foam. (1.84 g, 88%) APCI (AP−): 429.2 (M−H)⁻.

Step 4:2-(3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

2-(3-Fluoro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.57 g, 1.32 mmol) was dissolved in 10 mL EtOAc,and m-chloroperoxybenzoic acid (1.5 g, 5.3 mmol) was added in oneportion to the resulting mixture. The mixture was stirred at ambienttemperature for 3 hours, then diluted with 100 mL EtOAc, washed withsat. NaHCO₃ (3×100 mL), brine, dried with MgSO₄, filtered andconcentrated. The residue was purified by column chromatography onsilica gel eluting with 33% moving to 50% EtOAc in hexanes to yieldtitle compound as a yellow foam. (0.48 g, 75%) APCI (AP−): 461.2 (M−H)⁻.

Step 5: Pyrrolidine-2-carboxylicacid(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide

2-(3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.45 g, 0.93 mmol) was dissolved in 15 mL DCM and15 mL trifluoroacetic acid and the resulting mixture was stirred atambient temperature for 1 hour. The mixture was concentrated, and theresidue was redissolved in 100 mL EtOAc, washed with sat. NaCl, driedwith MgSO₄, filtered and concentrated to yield title compound as an oil.(0.27 g, 80%) APCI (AP−): 361.1 (M−H)⁻.

Step 6: Pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

Pyrrolidine-2-carboxylic acid(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide (0.27 g, 0.75 mmol)and (5-Chloro-pyridin-2-yl)-carbamic acid 4-nitro-phenyl ester (0.22 g,0.0.75 mmol; see Example 3, step 3a) were combined in 10 mL DMF andheated at 80° C. for 4 hours, then cooled. 200 mL of water were thenadded and a precipitate formed. The solids were filtered off, washedwith water, redissolved in EtOAc, dried with MgSO₄, filtered andconcentrated. The residue was purified by column chromatography onsilica gel eluting with 70% EtOAc in hexanes to yield title compound.(220 mg, 57%) APCI (AP−): 515.1, 517.1 (M−H)⁻.

EXAMPLE 12 Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

Step 1: Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester

DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H₂O (2:1),and 87 mL of a 2M NaOH solution was added to the resulting mixture,followed by Boc₂O (24.6 g, 113 mmol). The mixture was stirred at ambienttemperature overnight. THF was removed in vacuo, and the remaining waterwas acidified to pH 3 with citric acid, then extracted twice with EtOAc.The combined organic layers were washed with water, brine, dried withMgSO₄, filtered and concentrated to yield title compound as a whitesolid. (18.7 g, quant.) APCI (AP−): 214.1 (M−H)⁻.

Step 2: 2-(4-Bromo-2-fluoro-phenylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (3.8 g, 18 mmol)was dissolved in 150 mL dry diethyl ether under Ar, and the resultingsolution was cooled in an ice water bath, while dry pyridine (8.6 mL,106 mmol) was added, followed by the dropwise addition of oxalylchloride (4.6 ML, 53 mmol). A precipitate formed immediately. Thereaction was stirred vigorously at 0° C. for one hour, then at ambienttemperature for one hour. 100 mL of diethyl ether were then added, andthe solids were removed by filtration washing with diethyl ether.Concentrated the filtrates to an off-white oil. Redissolved oil in 50 mLdry DCM under Ar, cooled to 0° C., added 6 mL pyridine followed by4-bromo-2-fluoroaniline (3.4 g, 17.7 mmol). The reaction was allowed towarm to ambient temperature, stirred for 3 hours then concentrated.Redissolved in 250 mL EtOAc, washed with 10% HCl (3×100 mL), brine (100mL), dried with MgSO₄, filtered and concentrated. Purified on a silicagel column eluted with 20% moving to 40% EtOAc in hexanes. Combined andconcentrated pure fractions to yield title compound as a white solid.(3.2 g, 47%) APCI (AP−): 385.1, 387.1 (M−H)⁻.

Step 3:2-(3-Fluoro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

2-(4-Bromo-2-fluoro-phenylcarbamoyl)-pyrrolidine-1-carboxylic acidtert-butyl ester (2 g, 4.8 mmol), 2-(methylthio)benzene boronic acid(0.98 g, 5.8 mmol), and tetrabutylammonium bromide (78 mg, 0.24 mmol)were combined in 30 mL toluene, added 5 mL of a 2M aqueous Na₂CO₃solution followed by tetrakistriphenylphosphine palladium(0) (0.28 g,0.24 mmol). Heated reaction at reflux for 4 hours, cooled, concentrated,redissolved in EtOAc (250 mL), washed with water (3×200 mL), brine (200mL), dried with MgSO₄, filtered, and concentrated in the presence of 4 gcoarse silica. Loaded silica onto a silica gel column, eluted with 20%EtOAc in hexanes. Combined and concentrated pure fractions to yieldtitle compound as a yellow foam. (1.84 g, 88%) APCI (AP−): 429.2 (M−H)⁻.

Step 4:2-(3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

2-(3-Fluoro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (1.2 g, 2.8 mmol) was dissolved in 30 mL EtOAc,added m-chloroperoxybenzoic acid (3.2 g, 11 mmol) in one portion andstirred at ambient temperature for 3 hours. A 10% aqueous solution (50mL) of Na₂S₂O₃ was added to the vigorously stirring reaction in order toquench peroxide. After 30 minutes the solution was diluted with 100 mLEtOAc, separated layers, washed organics with sat. NaHCO₃ (3×100 mL),brine, dried with MgSO₄, filtered and concentrated. Purified on a silicagel column eluted with 50% EtOAc in hexanes. Combined and concentratedpure fractions to yield title compound as a yellow foam. (1.01 g, 78%)APCI (AP−): 461.1 (M−H)⁻.

Step 5: Pyrrolidine-2-carboxylic acid(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide

2-(3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (1 g, 2 mmol) was dissolved in 20 mL DCM and 10 mLtrifluoroacetic acid and stirred at ambient temperature for 1 hour.Concentrated solution, redissolved in 100 mL CHCl₃, repeated CHCl₃co-concentration 3 times to yield title compound as an oil. (quant.yield) APCI (AP−): 361.1 (M−H)⁻.

Step 6: Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

Pyrrolidine-2-carboxylic acid(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide (0.23 g, 0.64 mmol)was dissolved in 10 mL THF, added diisopropylethylamine (0.33 mL, 1.9mmol), followed by 4-chlorophenylisocyanate (97 mg, 0.64 mmol). Stirredreaction at ambient temperature for 1 hour then concentrated. Purifiedon a silica gel column eluted with 70% EtOAc in hexanes. Pure fractionswere combined and concentrated, redissolved in acetonitrile/water andlyophilized to yield title compound as a white powder. (0.23 g, 70%)APCI (AP−): 514.1, 516.1 (M−H)⁻.

EXAMPLE 13 Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[5-(2-sulfamoyl-phenyl)-pyridin-2-yl]-amide}

Step 1: Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester

DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H₂O (2:1),added 87 mL of a 2M NaOH solution followed by Boc₂O (24.6 g, 113 mmol).Stirred at ambient temperature overnight. Removed THF in vacuo,acidified water to pH 3 with citric acid, extracted twice with EtOAc,washed organics with water, brine, dried with MgSO₄, filtered andconcentrated to yield title compound as a white solid. (18.7 g, quant.)APCI (AP−): 214.1 (M−H)⁻.

Step 2: 2-(5-Bromo-pyridin-2-ylcarbamoyl)-pyrrolidine-1-carboxylic acidtert-butyl ester

Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.97 g, 9.2 mmol)was dissolved in 150 mL dry diethyl ether under Ar, cooled in an icewater bath, added dry pyridine (3.7 mL, 45.8 mmol) followed by thedropwise addition of oxalyl chloride (2 mL, 22.9 mmol). A precipitateforms immediately. The reaction was stirred vigorously at 0° C. for 2hours, then at ambient temperature for one hour. Added 100 mL diethylether, filtered off solids washing with diethyl ether. Concentrated thefiltrates to an off-white oil. Redissolved oil in 100 mL dry DCM underAr, cooled to 0° C., added 3 mL pyridine followed by2-amino-5-bromopyridine (1.32 g, 7.6 mmol). The reaction was allowed towarm to ambient temperature, stirred for 3 hours then concentrated.Redissolved in 250 mL EtOAc, washed with 10% HCl (3×100 mL), brine (100mL), dried with MgSO₄, filtered and concentrated to yield title compoundas a yellow sticky solid. (2.74 g, 97%) APCI (AP−): 368.0, 370.0 (M−H)⁻.

Step 3:2-[5-(2-tert-Butylsulfamoyl-phenyl)-pyridin-2-ylcarbamoyl]-pyrrolidine-1-carboxylicacid tert-butyl ester

2-(5-Bromo-pyridin-2-ylcarbamoyl)-pyrrolidine-1-carboxylic acidtert-butyl ester (0.92 g, 2.48 mmol), 2-(N-tert-butyl)phenylsulfonamideboronic acid (0.64 g, 2.48 mmol), and tetrabutylammonium bromide (40 mg,0.12 mmol) were combined in 10 mL toluene, added 2 mL of an aqueous 2Msodium carbonate solution followed by the addition oftetrakistriphenylphosphine palladium(0) (144 mg, 0.12 mmol). Refluxedsolution for 4 hours, cooled to room temperature, partitioned betweenEtOAc (150 mL) and water (100 mL), washed organics with water (3×100mL), brine, dried with MgSO₄, filtered and concentrated. Purified on asilica gel column eluted with 40% moving to 50% EtOAc in hexanes.Combined and concentrated pure fractions to yield title compound as awhite solid. (0.92 g, 74%) APCI (AP−): 501.1 (M−H)⁻.

Step 4: Pyrrolidine-2-carboxylic acid[5-(2-tert-butylsulfamoyl-phenyl)-pyridin-2-yl]-amide

2-[5-(2-tert-Butylsulfamoyl-phenyl)-pyridin-2-ylcarbamoyl]-pyrrolidine-1-carboxylicacid tert-butyl ester (0.92 g, 1.83 mmol) was dissolved in 30 mL DCM,added 10 mL trifluoroacetic acid and stirred at ambient temperature forone hour. Concentrated solution, redissolved in CHCl₃ andreconcentrated. Repeated co-concentration twice to yield title compoundas an oil. (quant. yield) APCI (AP−): 401.1 (M−H)⁻.

Step 5: Pyrrolidine-1,2-dicarboxylic acid2-{[5-(2-tert-butylsulfamoyl-phenyl)-pyridin-2-yl]-amide}1-[(4-chloro-phenyl)-amide]

Pyrrolidine-2-carboxylic acid[5-(2-tert-butylsulfamoyl-phenyl)-pyridin-2-yl]-amide (0.44 g, 0.59mmol) was dissolved in 10 mL THF, added diisopropylethylamine (0.41 mL,2.4 mmol) followed by 4-chlorophenylisocyanate (91 mg, 0.59 mmol).Stirred at ambient temperature for 2 hours. Diluted reaction with 50 mLEtOAc, washed with 10% citric acid (3×50 mL), water (2×50 mL), brine,dried with MgSO₄, filtered and concentrated to yield title compound.(0.28 g, 85%) APCI (AP+): 556.2, 558.2 (M−H)⁺.

Step 6: Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[5-(2-sulfamoyl-phenyl)-pyridin-2-yl]-amide}

Pyrrolidine-1,2-dicarboxylic acid2-{[5-(2-tert-butylsulfamoyl-phenyl)-pyridin-2-yl]-amide}1-[(4-chloro-phenyl)-amide](0.28 g, 0.5 mmol) was stirred in 10 mL trifluoroacetic acid at ambienttemperature for 20 hours. The solution was concentrated and purified ona silica gel column using an automated system with gradient of 40-100%EtOAc in hexanes over 40 minutes. Combined and concentrated purefractions, redissolved in acetonitrile/water and lyophilized to yieldtitle compound as a light yellow powder. (0.156 g, 62%) APCI (AP+):500.0, 501.9 (M+H)⁺.

EXAMPLE 14 Pyrrolidine-1,2-dicarboxylic acid2-[(3-chloro-2′-methanesulfonyl-biphenyl-4-yl)-amide]1-[(5-chloro-pyridin-2-yl)-amide]

Step 1: Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester

DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H₂O (2:1),added 87 mL of a 2M NaOH solution followed by Boc₂O (24.6 g, 113 mmol).Stirred at ambient temperature overnight. Removed THF in vacuo,acidified water to pH 3 with citric acid, extracted twice with EtOAc,washed organics with water, brine, dried with MgSO4, filtered andconcentrated to yield title compound as a white solid. (18.7 g, quant.)APCI (AP−): 214.1 (M−H)⁻.

Step 2: 2-(4-Bromo-2-chloro-phenylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.2 g, 10 mmol)was dissolved in 150 mL dry diethyl ether under Ar, cooled in an icewater bath, added dry pyridine (2.8 mL, 34 mmol) followed by thedropwise addition of oxalyl chloride (1.5 mL, 17 mmol). A precipitateforms immediately. The reaction was stirred vigorously at 0° C. for 1hours, then at ambient temperature for two hours. Added 100 mL diethylether, filtered off solids washing with diethyl ether. Concentrated thefiltrates to an off-white oil. Redissolved oil in 100 mL dry DCM underAr, cooled to 0° C., added 3 mL pyridine followed by2-chloro-4-bromoaniline (1.8 g, 8.5 mmol). The reaction was allowed towarm to ambient temperature and stirred over the weekend. Concentratedreaction, redissolved in 250 mL EtOAc, washed with 10% citric acid(3×100 mL), water, (2×100 mL), brine (100 mL), dried with MgSO₄,filtered and concentrated. Purified on a silica gel column eluted withan automated system with gradient of 0-60% EtOAc in hexanes. Combinedand concentrated pure fractions to yield title compound as a yellowsolid. (2.7 g, 79%) APCI (AP−): 401.0, 403.0, 405.0 (M−H)⁻.

Step 3:2-(3-Chloro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

2-(4-Bromo-2-chloro-phenylcarbamoyl)-pyrrolidine-1-carboxylic acidtert-butyl ester (1 g, 2.5 mmol), 2-(methylthio)benzene boronic acid(0.5 g, 3 mmol), and tetrabutylammonium bromide (40 mg, 0.12 mmol) werecombined in 10 mL toluene, added 2 mL of a 2M aqueous Na2CO3 solutionfollowed by tetrakistriphenylphosphine palladium(0) (0.14 g, 0.12 mmol).Heated reaction at reflux for 5 hours, cooled, dissolved in EtOAc (150mL), washed with water (3×50 mL), brine (50 mL), dried with MgSO₄,filtered, and concentrated. Purified on a silica gel column eluted usingan automated system with gradient of 0-50% EtOAc in hexanes over 40minutes. Combined and concentrated pure fractions to yield titlecompound as a white foam. (1.01 g, 91%) APCI (AP−): 445.1, 447.1 (M−H)⁻.

Step 4:2-(3-Chloro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

2-(3-Chloro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (1 g, 2 mmol) was dissolved in 20 mL EtOAc, addedm-chloroperoxybenzoic acid (2.6 g, 8.9 mmol) in one portion and stirredat ambient temperature for 3 hours. A 10% aqueous solution (30 mL) ofNa₂S₂O₃ was added to the vigorously stirring reaction in order to quenchperoxide. After 20 minutes the solution was diluted with 100 mL EtOAc,separated layers, washed organics with sat. NaHCO₃ (3×100 mL), brine,dried with MgSO₄, filtered and concentrated to yield title compound as aclear oil. (1 g, 100%) APCI (AP−): 477.1, 479.1 (M−H)⁻.

Step 5: Pyrrolidine-2-carboxylic acid(3-chloro-2′-methanesulfonyl-biphenyl-4-yl)-amide

2-(3-Chloro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (1 g, 2 mmol) was dissolved in 20 mL DCM and 20 mLtrifluoroacetic acid and stirred at ambient temperature for 2 hours.Concentrated solution, redissolved in 100 mL CHCl₃, repeated CHCl₃co-concentration 4 times to yield title compound as a yellow foam.(quant. yield) APCI (AP+): 379.1, 381.1 (M+H)⁺.

Step 6: Pyrrolidine-1,2-dicarboxylic acid2-[(3-chloro-2′-methanesulfonyl-biphenyl-4-yl)-amide]1-[(5-chloro-pyridin-2-yl)-amide]

Pyrrolidine-2-carboxylic acid(3-chloro-2′-methanesulfonyl-biphenyl-4-yl)-amide (0.11 g, 0.29 mmol)and (5-Chloro-pyridin-2-yl)-carbamic acid 4-nitro-phenyl ester (0.085 g,0.29 mmol; see Example 3, step 3a) were combined in 3 mL DMF and heatedat 50° C. for 2 hours, dissolved in 100 mL EtOAc, washed with sat.NaHCO₃ (3×50 mL), brine, dried with MgSO₄, filtered and concentrated.Purified on a silica gel column eluting using an automated system withgradient of 0-100% EtOAc in hexanes over 40 minutes. Combined andconcentrated pure fractions, redissolved in acetonitrile/water andlyophilized to yield title compound as a white powder. (110 mg, 71%)APCI (AP+): 533.0, 535.0 (M+H)⁺.

EXAMPLE 15 Pyrrolidine-1,2-dicarboxylic acid2-[(3-chloro-2′-methanesulfonyl-biphenyl-4-yl)-amide]1-[(4-chloro-phenyl)-amide]

Step 1: Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester

DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H₂O (2:1),added 87 mL of a 2M NaOH solution followed by Boc₂O (24.6 g, 113 mmol).Stirred at ambient temperature overnight. Removed THF in vacuo,acidified water to pH 3 with citric acid, extracted twice with EtOAc,washed organics with water, brine, dried with MgSO₄, filtered andconcentrated to yield title compound as a white solid. (18.7 g, quant.)APCI (AP−): 214.1 (M−H)⁻.

Step 2: 2-(4-Bromo-2-chloro-phenylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.2 g, 10 mmol)was dissolved in 150 mL dry diethyl ether under Ar, cooled in an icewater bath, added dry pyridine (2.8 mL, 34 mmol) followed by thedropwise addition of oxalyl chloride (1.5 mL, 17 mmol). A precipitateforms immediately. The reaction was stirred vigorously at 0° C. for 1hours, then at ambient temperature for two hours. Added 100 mL diethylether, filtered off solids washing with diethyl ether. Concentrated thefiltrates to an off-white oil. Redissolved oil in 100 mL dry DCM underAr, cooled to 0° C., added 3 mL pyridine followed by2-chloro-4-bromoaniline (1.8 g, 8.5 mmol). The reaction was allowed towarm to ambient temperature and stirred over the weekend. Concentratedreaction, redissolved in 250 mL EtOAc, washed with 10% citric acid(3×100 mL), water, (2×100 mL), brine (100 mL), dried with MgSO₄,filtered and concentrated. Purified on a silica gel column eluted withan automated system with gradient of 0-60% EtOAc in hexanes. Combinedand concentrated pure fractions to yield title compound as a yellowsolid. (2.7 g, 79%) APCI (AP−): 401.0, 403.0, 405.0 (M−H)⁻.

Step 3:2-(3-Chloro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

2-(4-Bromo-2-chloro-phenylcarbamoyl)-pyrrolidine-1-carboxylic acidtert-butyl ester (1 g, 2.5 mmol), 2-(methylthio)benzene boronic acid(0.5 g, 3 mmol), and tetrabutylammonium bromide (40 mg, 0.12 mmol) werecombined in 10 mL toluene, added 2 mL of a 2M aqueous Na₂CO₃ solutionfollowed by tetrakistriphenylphosphine palladium(0) (0.14 g, 0.12 mmol).Heated reaction at reflux for 5 hours, cooled, dissolved in EtOAc (150mL), washed with water (3×50 mL), brine (50 mL), dried with MgSO₄,filtered, and concentrated. Purified on a silica gel column eluted usingan automated system with gradient of 0-50% EtOAc in hexanes over 40minutes. Combined and concentrated pure fractions to yield titlecompound as a white foam. (1.01 g, 91%) APCI (AP−): 445.1, 447.1 (M−H)⁻.

Step 4:2-(3-Chloro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

2-(3-Chloro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (1 g, 2 mmol) was dissolved in 20 mL EtOAc, addedm-chloroperoxybenzoic acid (2.6 g, 8.9 mmol) in one portion and stirredat ambient temperature for 3 hours. A 10% aqueous solution (30 mL) ofNa₂S₂O₃ was added to the vigorously stirring reaction in order to quenchperoxide. After 20 minutes the solution was diluted with 100 mL EtOAc,separated layers, washed organics with sat. NaHCO₃ (3×100 mL), brine,dried with MgSO₄, filtered and concentrated to yield title compound as aclear oil. (1 g, 100%) APCI (AP−): 477.1, 479.1 (M−H)⁻.

Step 5: Pyrrolidine-2-carboxylic acid(3-chloro-2′-methanesulfonyl-biphenyl-4-yl)-amide

2-(3-Chloro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (1 g, 2 mmol) was dissolved in 20 ML DCM and 20 mLtrifluoroacetic acid and stirred at ambient temperature for 2 hours.Concentrated solution, redissolved in 100 mL CHCl₃, repeated CHCl₃co-concentration 4 times to yield title compound as a yellow foam.(quant. yield) APCI (AP+): 379.1, 381.1 (M+H)⁺.

Step 6: Pyrrolidine-1,2-dicarboxylic acid2-[(3-chloro-2′-methanesulfonyl-biphenyl-4-yl)-amide]1-[(4-chloro-phenyl)-amide]

Pyrrolidine-2-carboxylic acid(3-chloro-2′-methanesulfonyl-biphenyl-4-yl)-amide (0.16 g, 0.42 mmol)was dissolved in 5 mL THF, added diisopropylethylamine (0.22 mL, 1.3mmol) followed by 4-chlorophenylisocyanate (65 mg, 0.42 mmol). Stirredat ambient temperature for 20 hours. The reaction was concentrated andpurified using an automated system with gradient of 0-100% EtOAc inhexanes over 40 minutes. Combined and concentrated pure fractions,redissolved in acetonitrile/water and lyophilized to yield titlecompound as a white powder. (0.175 g, 78%) APCI (AP+): 532.0,534.0(M−H)⁺.

EXAMPLE 16 Pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[5-(2-sulfamoyl-phenyl)-pyridin-2-yl]-amide}

Step 1: Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester

DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H₂O (2:1),added 87 mL of a 2M NaOH solution followed by Boc₂O (24.6 g, 113 mmol).Stirred at ambient temperature overnight. Removed THF in vacuo,acidified water to pH 3 with citric acid, extracted twice with EtOAc,washed organics with water, brine, dried with MgSO₄, filtered andconcentrated to yield title compound as a white solid. (18.7 g, quant.)APCI (AP−): 214.1 (M−H)⁻.

Step 2: 2-(5-Bromo-pyridin-2-ylcarbamoyl)-pyrrolidine-1-carboxylic acidtert-butyl ester

Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.97 g, 9.2 mmol)was dissolved in 150 mL dry diethyl ether under Ar, cooled in an icewater bath, added dry pyridine (3.7 mL, 45.8 mmol) followed by thedropwise addition of oxalyl chloride (2 mL, 22.9 mmol). A precipitateforms immediately. The reaction was stirred vigorously at 0° C. for 2hours, then at ambient temperature for one hour. Added 100 mL diethylether, filtered off solids washing with diethyl ether. Concentrated thefiltrates to an off-white oil. Redissolved oil in 100 mL dry DCM underAr, cooled to 0° C., added 3 mL pyridine followed by2-amino-5-bromopyridine (1.32 g, 7.6 mmol). The reaction was allowed towarm to ambient temperature, stirred for 3 hours then concentrated.Redissolved in 250 mL EtOAc, washed with 10% HCl (3×100 mL), brine (100mL), dried with MgSO₄, filtered and concentrated to yield title compoundas a yellow sticky solid. (2.74 g, 97%) APCI (AP−): 368.0, 370.0 (M−H)⁻.

Step 3:2-[5-(2-tert-Butylsulfamoyl-phenyl)-pyridin-2-ylcarbamoyl]-pyrrolidine-1-carboxylicacid tert-butyl ester

2-(5-Bromo-pyridin-2-ylcarbamoyl)-pyrrolidine-1-carboxylic acidtert-butyl ester (0.92 g, 2.48 mmol), 2-(N-tert-butyl)phenylsulfonamideboronic acid (0.64 g, 2.48 mmol), and tetrabutylammonium bromide (40 mg,0.12 mmol) were combined in 10 mL toluene, added 2 mL of an aqueous 2Msodium carbonate solution followed by the addition oftetrakistriphenylphosphine palladium(0) (144 mg, 0.12 mmol). Refluxedsolution for 4 hours, cooled to room temperature, partitioned betweenEtOAc (150 mL) and water (100 mL), washed organics with water (3×100mL), brine, dried with MgSO₄, filtered and concentrated. Purified on asilica gel column eluted with 40% moving to 50% EtOAc in hexanes.Combined and concentrated pure fractions to yield title compound as awhite solid. (0.92 g, 74%) APCI (AP−): 501.1 (M−H)⁻.

Step 4: Pyrrolidine-2-carboxylic acid[5-(2-tert-butylsulfamoyl-phenyl)-pyridin-2-yl]-amide

2-[5-(2-tert-Butylsulfamoyl-phenyl)-pyridin-2-ylcarbamoyl]-pyrrolidine-1-carboxylicacid tert-butyl ester (0.92 g, 1.83 mmol) was dissolved in 30 mL DCM,added 10 mL trifluoroacetic acid and stirred at ambient temperature forone hour. Concentrated solution, redissolved in CHCl₃ andreconcentrated. Repeated co-concentration twice to yield title compoundas an oil. (quant. yield) APCI (AP−): 401.1 (M−H)⁻.

Step 5: Pyrrolidine-1,2-dicarboxylic acid2-{[5-(2-tert-butylsulfamoyl-phenyl)-pyridin-2-yl]-amide}1-[(5-chloro-pyridin-2-yl)-amide]

Pyrrolidine-2-carboxylic acid[5-(2-tert-butylsulfamoyl-phenyl)-pyridin-2-yl]-amide (0.17 g, 0.25mmol) and (5-Chloro-pyridin-2-yl)-carbamic acid 4-nitro-phenyl ester(0.074 g, 0.25 mmol; see Example 3, step 3a) were combined in 3 mL DMF,added diisopropylethylamine (0.18 mL, 1 mmol) and heated at 50° C. for 2hours. Dissolved in 100 mL EtOAc, washed with sat. NaHCO₃ (3×50 mL),brine, dried with MgSO₄, filtered and concentrated. Purified on a silicagel column eluting using an automated system with gradient of 30-100%EtOAc in hexanes over 40 minutes. Combined and concentrated purefractions to yield title compound as a white solid. (90 mg, 64%) APCI(AP−): 555.2, 557.2 (M−H)⁻.

EXAMPLE 17 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

Step 1: (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester

Cis-4-hydroxy-D-proline (1.1 g, 8.4 mmol) was dissolved in 18 mL ofTHF/H₂O (2:1), added 2M aqueous NaOH solution (6.3 mL, 13 mmol),followed by Boc₂O. Reaction was stirred at ambient temperature over theweekend. Solution was taken up in 150 mL EtOAc, washed with 10% HCl(3×100 mL), dried organics with MgSO₄, filtered and concentrated toyield title compound as a white foam. (1.5 g, 77%) APCI (AP−): 230.1(M−H)⁻.

Step 2:(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester(1.5 g, 6.5 mmol) was dissolved in 20 mL DMF, added imidazole (1.1 g, 16mmol), dimethylaminopyridine (80 mg, 0.65 mmol), andtert-butyldimethylsilyl chloride (1.08 g, 7.1 mmol). Stirred at ambienttemperature overnight, dissolved in 150 mL EtOAc, washed with 10% citricacid (3×100 mL), water (2×100 mL), brine, dried with MgSO₄, filtered,and concentrated. Redissolved in 50 mL CHCl₃ and reconcentrated to yieldtitle compound as a clear oil. (1.54 g, 69%) APCI (AP−): 344.2 (M−H)⁻.

Step 3:(2R,4R)-2-(4-Bromo-2-fluoro-phenylcarbamoyl)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester

(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester (1.54 g, 4.5 mmol) was dissolved in 50 mLdiethyl ether under an Ar atmosphere, cooled in an ice water bath, addeddry pyridine (1.4 mL, 17.8 mmol), followed by the dropwise addition ofoxalyl chloride (0.58 mL, 6.7 mmol). Reaction was stirred at 0° C. for 1hour, then at ambient temperature for 1 hour. Diluted reaction with 50mL diethyl ether, filtered off solids and concentrated filtrates.Redissolved filtrate in 30 mL dry DCM under an Ar atmosphere, cooled inan ice water bath, added 1 mL dry pyridine followed by4-bromo-2-fluoroaniline (0.85 g, 4.5 mmol). Stirred reaction at ambienttemperature for 20 hours. Concentrated solution, redissolved in EtOAc(150 mL), washed with 10% citric acid (3×100 mL), water (2×100 mL),brine, dried with MgSO₄, filtered and concentrated. Purified on a silicagel column eluting with an automated system with gradient of 0-60% EtOAcin hexanes over 40 minutes. Combined and concentrated pure fractions toyield title compound as a clear oil. (0.96 g, 42%) APCI (AP−): 515.1,517.1 (M−H)⁻.

Step 4:(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

(2R,4R)-2-(4-Bromo-2-fluoro-phenylcarbamoyl)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.95 g, 1.84 mmol), 2-(methylthio)benzene boronicacid (0.37 g, 2.2 mmol), and tetrabutylammonium bromide (30 mg, 0.09mmol) were combined in 15 mL toluene, added 2 mL of a 2M aqueous Na2CO3solution followed by tetrakistriphenylphosphine palladium(0) (0.11 g,0.09 mmol). Heated reaction at reflux for 5 hours, cooled, dissolved inEtOAc (100 mL), washed with water (3×50 mL), brine (50 mL), dried withMgSO₄, filtered, and concentrated. Purified on a silica gel columneluted using an automated system with gradient of 0-60% EtOAc in hexanesover 40 minutes. Combined and concentrated pure fractions to yield titlecompound as a light yellow foam. (0.77 g, 74%) APCI (AP−): 559.3 (M−H)⁻.

Step 5:(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.84 g, 1.35 mmol) was dissolved in 20 mL EtOAc,added added m-chloroperoxybenzoic acid (1.6 g, 5.4 mmol) in one portionand stirred at ambient temperature for 3 hours. A 10% aqueous solution(50 mL) of Na₂S₂O₃ was added to the vigorously stirring reaction inorder to quench peroxide. After 20 minutes the solution was diluted with100 mL EtOAc, separated layers, washed organics with sat. NaHCO₃ (3×100mL), water (2×100 mL), brine, dried with MgSO₄, filtered andconcentrated to yield title compound as a light brown foam. (0.8 g,100%) APCI (AP−): 591.3 (M−H)⁻.

Step 6: (2R,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide

(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.8 g, 1.35 mmol) was dissolved in 30 mL DCM,added 10 mL trifluoroacetic acid and stirred reaction at ambienttemperature for 90 minutes. Solution was concentrated to yield titlecompound as an amber oil. (100% crude yield) APCI (AP−): (M−H)⁻.

Step 7: (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

(2R,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide (0.51 g, 1.35 mmol)was dissolved in 20 mL THF, added diisopropylethylamine (0.94 mL, 5.4mmol) followed by 4-chlorophenylisocyanate (0.21 g, 1.35 mmol). Stirredat ambient temperature for 2 hours. The reaction was dissolved in 100 mLEtOAc, washed with 10% citric acid (3×50 mL), water (2×50 mL), brine,dried with MgSO₄, filtered and concentrated. Purified using an automatedsystem with gradient of 50-100% EtOAc in hexanes over 40 minutes.Compound was still eluting at end of run. Switched gradient to 0-15%MeOH in EtOAc over 40 minutes. Combined and concentrated pure fractionsto yield title compound as a white solid. (0.54 g, 75%) APCI (AP+):530.1, 532.1(M−H)⁺.

EXAMPLE 18 Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)-phenyl]-amide}

Step 1: Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester

DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H₂O (2:1),added 87 mL of a 2M NaOH solution followed by Boc₂O (24.6 g, 113 mmol).Stirred at ambient temperature overnight. Removed THF in vacuo,acidified water to pH 3 with citric acid, extracted twice with EtOAc,washed organics with water, brine, dried with MgSO₄, filtered andconcentrated to yield title compound as a white solid. (18.7 g, quant.)APCI (AP−): 214.1 (M−H)⁻.

Step 2: 2-(4-Cyano-phenylcarbamoyl)-pyrrolidine-1-carboxylic acidtert-butyl ester

Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.1 g, 9.8 mmol)was dissolved in 100 mL dry diethyl ether under an argon atmosphere,added dry pyridine (3.3 mL, 32.5 mmol), cooled to 0° C. then addedoxalyl chloride (1.4 mL, 16.3 mmol) dropwise. A precipitate formsimmediately upon addition of oxalyl chloride and therefore reactionrequires vigorous stirring. Stirred at 0° C. for one hour than atambient temperature for 2 hours. Dry diethyl ether (100 ML) was addedand the solids were filtered off, washing with more diethyl ether. Thefiltrates were concentrated, then redissolved in dry DCM under argon,cooled to 0° C., added 1 mL dry pyridine then added 4-amino-benzonitrile(0.96 g, 8.1 mmol) in one portion. Stirred at ambient temperature for 2hours, concentrated, redissolved in ethyl acetate (250 mL), washed with10% citric acid (3×100 mL), water, brine, dried with MgSO₄, filtered andconcentrated to yield title compound as a white foam. (2.4 g, 93%) APCI(AP−): 314.1 (M−H)⁻.

Step 3: Pyrrolidine-2-carboxylic acid (4-cyano-phenyl)-amide

2-(4-Cyano-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butylester (3 g, 8 mmol) was dissolved in 90 mL of a 1:2 mixture oftrifluoroacetic acid and dichloromethane. The reaction was stirred atambient temperature for one hour then concentrated to yield titlecompound as an amber oil which was carried onto next step as is. APCI(AP−): 214.1 (M−H)⁻.

Step 4: Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-cyano-phenyl)-amide]

Pyrrolidine-2-carboxylic acid (4-cyano-phenyl)-amide (0.9 g, 4 mmol) wasdissolved in 25 mL tetrahydrofuran, added diisopropylethylamine (3.5 mL,20 mmol), followed by the addition of 4-chlorophenylisocyanate (0.61 g,4 mmol). The reaction was stirred at ambient temperature for one hourthen concentrated solution. Redissolved in 100 mL ethyl acetate, washedwith 10% citric acid (2×100 mL), water, brine, dried with MgSO₄,filtered and concentrated. Recrystallized from ethyl acetate and hexanesto yield title compound as a white powder. (1.1 g, 75%) APCI (AP−):367.1, 369.1 (M−H)⁻.

Step 5: Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)-phenyl]-amide}

Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-cyano-phenyl)-amide] (0.2 g, 0.54 mmol)was dissolved in 2 mL dry methanol under argon, cooled in an ice bath,bubbled in HCl(g) for 10 minutes, removed argon line and HCl line andsealed off flask. Stirred at 0° C. for 20 minutes, then at ambienttemperature for 4 hours. The solution was concentrated in vacuo to ayellow foam. The foam was redissolved in 4 mL dry methanol under argon,added N-methylethylenediamine (0.048 mL, 0.54 mmol) and stirred atambient temperature overnight. The solution was concentrated in vacuothen purified by preparatory HPLC. Combined and lyophilized purefractions to yield the TFA salt of the title compound as a white fluffypowder. (0.2 g, 69%) APCI (AP−): 424.1, 426.1 (M−H)⁻.

EXAMPLE 19 Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfonyl-biphenyl-4-yl)-amide]

Step 1: Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester

DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H₂O (2:1),added 87 mL of a 2M NaOH solution followed by Boc₂O (24.6 g, 113 mmol).Stirred at ambient temperature overnight. Removed THF in vacuo,acidified water to pH 3 with citric acid, extracted twice with EtOAc,washed organics with water, brine, dried with MgSO₄, filtered andconcentrated to yield title compound as a white solid. (18.7 g, quant.)APCI (AP−): 214.1 (M−H)⁻.

Step 2: 2-(4-Bromo-phenylcarbamoyl)-pyrrolidine-1-carboxylic acidtert-butyl ester

Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (5 g, 23 mmol) wasdissolved in 250 mL dry diethyl ether under Ar, cooled in an ice waterbath, added dry pyridine (11.3 mL, 139 mmol) followed by the dropwiseaddition of oxalyl chloride (6.1 mL, 69 mmol). A precipitate formsimmediately. The reaction was stirred vigorously at 0° C. for one hour,then at ambient temperature for one hour. Added 100 mL diethyl ether,filtered off solids washing with diethyl ether. Concentrated thefiltrates to an off white oil. Redissolved (3.66 g, 15 mmol) oil in 40mL dry DCM under Ar, cooled to 0° C., added 4.6 mL pyridine followed by4-bromoaniline (2.7 g, 15 mmol). The reaction was allowed to warm toambient temperature, stirred for 3 hours then concentrated. Redissolvedin 100 mL EtOAc, washed with 1 N HCl (2×100 mL), brine (100 mL), driedwith MgSO₄, filtered and concentrated to yield title compound. (4.56 g,80%) APCI (AP−): 369.0, 370.0 (M−H)⁻.

Step 3:2-(2′-Methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

2-(4-Bromo-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butylester (2.57 g, 6.9 mmol), 2-(methylthio)benzene boronic acid (1.4 g, 8.3mmol), and tetrabutylammonium bromide (110 mg, 0.33 mmol) were combinedin 30 mL toluene, added 6.9 mL of a 2M aqueous Na₂CO₃ solution followedby tetrakistriphenylphosphine palladium(0) (0.40 g, 0.34 mmol). Heatedreaction at reflux overnight, cooled, concentrated, redissolved in EtOAc(250 mL), washed with water (3×200 mL), brine (200 mL), dried withMgSO₄, filtered, and concentrated. Purified on a silica gel columneluted with 20% moving to 40% EtOAc in hexanes. Combined andconcentrated pure fractions to yield title compound. (1.75 g, 60%) APCI(AP−): 411.1 (M−H)⁻.

Step 4:2-(2′-Methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

2-(2′-Methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (1.0 g, 2.4 mmol) was dissolved in 10 mLacetonitrile, added oxone (2.98 g, 4.8 mmol) in one portion and stirredat ambient temperature for 1 week and then concentrated. Redissolved in100 mL EtOAc and 100 mL sat. NaHCO₃, separated layers, washed organicswith brine, dried with MgSO₄, filtered and concentrated. Purified on asilica gel column eluted with 20% moving to 40% EtOAc in hexanes.Combined and concentrated pure fractions to yield title compound. (0.80g, 75%) APCI (AP−): 443.1 (M−H)⁻.

Step 5: Pyrrolidine-2-carboxylic acid(2′-methanesulfonyl-biphenyl-4-yl)-amide

2-(2′-Methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.8 g, 1.7 mmol) was dissolved in 25 mL DCM and 5mL trifluoroacetic acid and stirred at ambient temperature for one hourand concentrated. Redissolved in 100 mL EtOAc and 100 mL sat. NaHCO₃,separated layers, washed organics with brine, dried with MgSO₄, filteredand concentrated to yield title compound as an oil (quant. yield) APCI(AP−): 343.1 (M−H)⁻.

Step 6: Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfonyl-biphenyl-4-yl)-amide]

Pyrrolidine-2-carboxylic acid (2′-methanesulfonyl-biphenyl-4-yl)-amide(0.61 g, 1.8 mmol) was dissolved in 20 mL THF, addeddiisopropylethylamine (0.92 mL, 5.3 mmol), followed by4-chlorophenylisocyanate (270 mg, 1.7 mmol). Stirred reaction at ambienttemperature for one hour then concentrated. Crystallized from EtOAc inhexanes and filtered to yield title compound as a white powder. (0.71 g,80%) APCI (AP−): 496.1, 498.1 (M−H)⁻.

EXAMPLE 20 Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfonyl-3-methyl-biphenyl-4-yl)-amide]

Step 1: Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester

DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H₂O (2:1),added 87 mL of a 2M NaOH solution followed by Boc₂O (24.6 g, 113 mmol).Stirred at ambient temperature overnight. Removed THF in vacuo,acidified water to pH 3 with citric acid, extracted twice with EtOAc,washed organics with water, brine, dried with MgSO₄, filtered andconcentrated to yield title compound as a white solid. (18.7 g, quant.)APCI (AP−): 214.1 (M−H)⁻.

Step 2: 2-(4-Bromo-2-methyl-phenylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2 g, 9.3 mmol) wasdissolved in 100 mL dry diethyl ether under Ar, cooled in an ice waterbath, added dry pyridine (4.5 mL, 55 mmol) followed by the dropwiseaddition of oxalyl chloride (2.4 mL, 27 mmol). A precipitate formsimmediately. The reaction was stirred vigorously at 0° C. for one hour,then at ambient temperature for one hour. Added 100 mL diethyl ether,filtered off solids washing with diethyl ether. Concentrated thefiltrates to an off white oil. Redissolved (0.95 g, 4.0 mmol) oil in 40mL dry DCM under Ar, cooled to 0° C., added 1.3 mL pyridine followed by4-bromo-2-methylaniline (0.75 g, 4.0 mmol). The reaction was allowed towarm to ambient temperature, stirred overnight then concentrated.Redissolved in 100 mL EtOAc, washed with 1 N HCl (3×50 mL), brine (100mL), dried with MgSO₄, filtered and concentrated to yield titlecompound. (1.09 g, 70%) APCI (AP−): 381.0, 383.0 (M−H)⁻.

Step 3:2-(3-Methyl-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

2-(4-Bromo-2-methyl-phenylcarbamoyl)-pyrrolidine-1-carboxylic acidtert-butyl ester (1.07 g, 2.7 mmol), 2-(methylthio)benzene boronic acid(0.56 g, 3.3 mmol), and tetrabutylammonium bromide (322 mg, 0.13 mmol)were combined in 20 mL toluene, added 2.8 mL of a 2M aqueous Na2CO3solution followed by tetrakistriphenylphosphine palladium(0) (0.161 g,0.13 mmol). Heated reaction at reflux 4 hours, cooled, concentrated,redissolved in EtOAc (250 mL), washed with water (3×200 mL), brine (200mL), dried with MgSO₄, filtered, and concentrated. Purified on a silicagel column eluted with 20% EtOAc in hexanes. Combined and concentratedpure fractions to yield title compound. (0.59 g, 50%) APCI (AP−): 425.1(M−H)⁻.

Step 4:2-(2′-Methanesulfonyl-3-methyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

2-(3-Methyl-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.57 g, 1.3 mmol) was dissolved in 10 mL EtOAc,added added m-chloroperoxybenzoic acid (1.76 g, 6.1 mmol) in one portionand stirred at ambient temperature for 3 hours. Reaction not complete.Concentrated and redissolved in 10 mL acetonitrile and added oxone (1. 5g, 2.4 mmol) in one portion and stirred at ambient temperature overnightand then concentrated. Redissolved in 100 mL EtOAc and 100 mL sat.NaHCO₃, separated layers, washed organics with brine, dried with MgSO₄,filtered and concentrated. Purified on a silica gel column eluted with20% moving to 40% EtOAc in hexanes. Combined and concentrated purefractions to yield title compound. (0.44 g, 72%) APCI (AP−): 457.1(M−H)⁻.

Step 5: Pyrrolidine-2-carboxylic acid(2′-methanesulfonyl-3-methyl-biphenyl-4-yl)-amide

2-(2′-Methanesulfonyl-3-methyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.4 g, 0.87 mmol) was dissolved in 15 mL DCM and5 mL trifluoroacetic acid and stirred at ambient temperature for 2 hourand concentrated. Redissolved in 100 mL EtOAc and 100 mL sat. NaHCO₃,separated layers, washed organics with brine, dried with MgSO₄, filteredand concentrated to yield title compound as an oil (0.29 g, 93%) APCI(AP−): 357.1 (M−H)⁻.

Step 6: Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfonyl-3-methyl-biphenyl-4-yl)-amide]

Pyrrolidine-2-carboxylic acid(2′-methanesulfonyl-3-methyl-biphenyl-4-yl)-amide (0.29 g, 0.80 mmol)was dissolved in 10 mL THF, added diisopropylethylamine (0.42 mL, 2.4mmol), followed by 4-chlorophenylisocyanate (124 mg, 0.80 mmol). Stirredreaction at ambient temperature for one hour then concentrated. Purifiedon a silica gel column eluted with 20% moving to 40% EtOAc in hexanes.Combined and concentrated pure fractions to yield title compound. (0.32g, 78%) APCI (AP−): 510.1, 512.1 (M−H)⁻

EXAMPLE 21 (2R,4R)-4-methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

Step 1: (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester

Cis-4-hydroxy-D-proline (1.1 g, 8.4 mmol) was dissolved in 18 ML ofTHF/H₂O (2:1), added 2M aqueous NaOH solution (6.3 mL, 13 mmol),followed by Boc₂O. Reaction was stirred at ambient temperature over theweekend. Solution was taken up in 150 mL EtOAc, washed with 10% HCl(3×100 mL), dried organics with MgSO₄, filtered and concentrated toyield title compound as a white foam. (1.5 g, 77%) APCI (AP−): 230.1(M−H)⁻.

Step 2:(2R,4R)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester(1.5 g, 6.5 mmol) was dissolved in 2 mL DMF, added imidazole (1.1 g, 16mmol), dimethylaminopyridine (80 mg, 0.65 mmol), andtert-butyldimethylsilyl chloride (1.08 g, 7.1 mmol). Stirred at ambienttemperature overnight, dissolved in 150 mL EtOAc, washed with 10% citricacid (3×100 mL), water (2×100 mL), brine, dried with MgSO₄, filtered,and concentrated. Redissolved in 50 ML CHCl₃ and reconcentrated to yieldtitle compound as a clear oil. (1.54 g, 69%) APCI (AP−): 344.2 (M−H)⁻.

Step 3:(2R,4R)-2-(4-bromo-2-fluoro-phenylcarbamoyl)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester

(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester (1.54 g, 4.5 mmol) was dissolved in 50 mLdiethyl ether under an Ar atmosphere, cooled in an ice water bath, addeddry pyridine (1.4 mL, 17.8 mmol), followed by the dropwise addition ofoxalyl chloride (0.58 mL, 6.7 mmol). Reaction was stirred at 0° C. for 1hour, then at ambient temperature for 1 hour. Diluted reaction with 50mL diethyl ether, filtered off solids and concentrated filtrates.Redissolved filtrate in 30 mL dry DCM under an Ar atmosphere, cooled inan ice water bath, added 1 mL dry pyridine followed by4-bromo-2-fluoroaniline (0.85 g, 4.5 mmol). Stirred reaction at ambienttemperature for 20 hours. Concentrated solution, redissolved in EtOAc(150 mL), washed with 10% citric acid (3×100 mL), water (2×100 mL),brine, dried with MgSO₄, filtered and concentrated. Purified on a silicagel column eluting with an automated system with gradient of 0-60% EtOAcin hexanes over 40 minutes. Combined and concentrated pure fractions toyield title compound as a clear oil. (0.96 g, 42%) APCI (AP−): 515.1,517.1 (M−H)⁻.

Step 4:(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

(2R,4R)-2-(4-Bromo-2-fluoro-phenylcarbamoyl)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.95 g, 1.84 mmol), 2-(methylthio)benzene boronicacid (0.37 g, 2.2 mmol), and tetrabutylammonium bromide (30 mg, 0.09mmol) were combined in 15 mL toluene, added 2 mL of a 2M aqueous Na₂CO₃solution followed by tetrakistriphenylphosphine palladium(0) (0.11 g,0.09 mmol). Heated reaction at reflux for 5 hours, cooled, dissolved inEtOAc (100 mL), washed with water (3×50 mL), brine (50 mL), dried withMgSO₄, filtered, and concentrated. Purified on a silica gel columneluted using an automated system with gradient of 0-60% EtOAc in hexanesover 40 minutes. Combined and concentrated pure fractions to yield titlecompound as a light yellow foam. (0.77 g, 74%) APCI (AP−): 559.3 (M−H)⁻.

Step 5:(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.84 g, 1.35 mmol) was dissolved in 20 mL EtOAc,added added m-chloroperoxybenzoic acid (1.6 g, 5.4 mmol) in one portionand stirred at ambient temperature for 3 hours. A 10% aqueous solution(50 mL) of Na₂S₂O₃ was added to the vigorously stirring reaction inorder to quench peroxide. After 20 minutes the solution was diluted with100 mL EtOAc, separated layers, washed organics with sat. NaHCO₃ (3×100mL), water (2×100 mL), brine, dried with MgSO₄, filtered andconcentrated to yield title compound as a light brown foam. (0.8 g,100%) APCI (AP−): 591.3 (M−H)⁻.

Step 6: (2R,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide

(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.8 g, 1.35 mmol) was dissolved in 30 mL DCM,added 10 mL trifluoroacetic acid and stirred reaction at ambienttemperature for 90 minutes. Solution was concentrated to yield titlecompound as an amber oil. (100% crude yield) APCI (AP−): 434.1 (M−H)⁻.

Step 7: (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

(2R,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide (0.51 g, 1.35 mmol)was dissolved in 20 mL THF, added diisopropylethylamine (0.94 mL, 5.4mmol) followed by 4-chlorophenylisocyanate (0.21 g, 1.35 mmol). Stirredat ambient temperature for 2 hours. The reaction was dissolved in 100 mLEtOAc, washed with 10% citric acid (3×50 mL), water (2×50 mL), brine,dried with MgSO₄, filtered and concentrated. Purified using an automatedsystem with gradient of 50-100% EtOAc in hexanes over 40 minutes.Compound was still eluting at end of run. Switched gradient to 0-15%MeOH in EtOAc over 40 minutes. Combined and concentrated pure fractionsto yield title compound as a white solid. (0.54 g, 75%) APCI (AP+):530.1, 532.1(M+H)⁺.

Step 8: (2R,4R)-4-methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

(2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide](0.070 g, 0.13 mmol) was dissolved in 1.5 mL dry acetonitrile under anArgon atmosphere. Freshly prepared Ag₂O (45mg, 0.19 mmol) was addedfollowed by methyl iodide (9 mL, 0.14 mmol). The reaction was stirredfor 2 hours with no reaction seen by HPLC. Added 10 equivalents each ofAg₂O and methyl iodide. After 2 hours the reaction was complete by HPLC.The solids were filtered through celite, washing with ethyl acetate. Thefiltrates were concentrated, then purified by preparatory HPLC. Purefractions were combined and lyophilized to yield title compound. (28 mg,40%) APCI (AP−): 544.0, 546.1 (M−H)⁻.

EXAMPLE 22 (2R)-4-oxo-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

Step 1: (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester

Cis-4-hydroxy-D-proline (15 g, 114 mmol) was dissolved In 150 mL ofTHF/H₂O (2:1), added 2M aqueous NaOH solution (86 μmL, 172 mmol),followed by Boc₂O (27 g, 126 mmol). Reaction was stirred at ambienttemperature overnight. The solution was acidified with 10% citric acidthen extracted with EtOAc (2×250 mL), washed with water, brine, driedorganics with MgSO₄, filtered and concentrated to yield title compound.(16 g, 61%) APCI (AP−): 230.1 (M−H)⁻.

Step 2:(2R,4R)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester(16 g, 69 mmol) was dissolved in 100 mL DMF, added imidazole (12 g, 173mmol), dimethylaminopyridine (0.85 g, 6.9 mmol), andtert-butyldimethylsilyl chloride (12.5 g, 83 mmol). Stirred at ambienttemperature overnight, dissolved in 350 mL EtOAc, washed with 10% citricacid (3×200 mL), water (2×200 mL), brine, dried with MgSO₄, filtered,and concentrated to yield title compound. (20 g, 84%) APCI (AP−): 344.2(M−H)⁻.

Step 3:(2R,4R)-2-(4-bromo-2-fluoro-phenylcarbamoyl)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester

(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester (4.45 g, 12.9 mmol) was dissolved in 50 mL dryCHCl₃ under an Ar atmosphere, added 4-bromo-2-fluoroaniline (2.45 g,12.9 mmol), EEDQ (3.8 g, 15 mmol), and triethylamine (2.6 mL, 19.3mmol). Reaction was refluxed for 6 hours, cooled and concentrated.Redissolved in EtOAc (250 mL), washed with 10% HCl (2×200 mL), 0.1M NaOH(2×200 mL), water, brine, dried with MgSO₄, filtered and concentrated toyield title compound. (5.5 g, 82%)

APCI (AP−): 515.1, 517.1 (M−H)⁻.

Step 4:(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

(2R,4R)-2-(4-Bromo-2-fluoro-phenylcarbamoyl)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester (5.7 g, 10 mmol), 2-(methylthio)benzene boronicacid (2.1 g, 12.6 mmol), and tetrabutylammonium bromide (0.17 g, 0.52mmol) were combined in 50 mL toluene, added 10 mL of a 2M aqueous Na₂CO₃solution followed by tetrakistriphenylphosphine palladium(0) (0.61 g,0.52 mmol). Heated reaction at reflux for 4 hours, cooled, dissolved inEtOAc (250 mL), washed with water (200 mL), brine, dried with MgSO₄,filtered, and concentrated in the presence of 15 g coarse silica.Slurried silica in mobile phase and loaded onto a silica gel column,eluted with 25% EtOAc in hexanes. Combined and concentrated fractions toyield title compound. (4.1 g, 70%) APCI (AP−): 559.3 (M−H)⁻.

Step 5:(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (4.1 g, 7.3 mmol) was dissolved in 20 mL EtOAc,added added m-chloroperoxybenzoic acid (7.2 g, 29 mmol) in one portionand stirred at ambient temperature for 3 hours. A 10% aqueous solution(50 mL) of Na₂S₂O₃ was added to the vigorously stirring reaction inorder to quench peroxide. After 20 minutes the solution was diluted with100 mL EtOAc, separated layers, washed organics with sat. NaHCO₃ (3×100mL), water (2×100 mL), brine, dried with MgSO₄, filtered andconcentrated to yield title compound. (4.3 g, 99%) APCI (AP−): 591.3(M−H)⁻.

Step 6: (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (3.25 g, 5.5 mmol) was dissolved in 50 mL DCM,added 25 mL trifluoroacetic acid and stirred reaction at ambienttemperature for 90 minutes. Solution was concentrated. The resulting oilwas dissolved in 75 mL THF, added triethylamine (3.8 mL, 5.4 mmol)followed by 4-chlorophenylisocyanate (0.84 g, 5.5 mmol). Stirred atambient temperature for 2 hours. The reaction was concentrated andpurified on a silica gel column eluted with straight ethyl acetateinitially moving to 5% MeOH in ethyl acetate. Combined and concentratedpure fractions to yield title compound. (2.5 g, 85%) APCI (AP−): 530.1,532.1(M−H)⁻.

Step 7: (2R)-4-oxo-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

(2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide](0.78 g, 1.5 mmol) was dissolved in 10 mL dry DCM under an Argonatmosphere, added 0.5 g celite, 0.5 g of 4 angstrom crushed molecularsieves, and pyridinium chlorochromate (0.47 g, 2.2 mmol). Stirred atambient temperature for 6 hours, reaction appears to have stalled. Added1 g pyridinium chlorochromate and stirred at RT overnight. HPLC did notchange. Added 40 mL of a 1:1 mixture of hexanes:Et2O. Filtered through afilter funnel with silica gel. Washed with DCM. Compound did not elute.Washed with DCM:MeOH (90:10). Concentrated filtrates. Suspect pyridiniumchlorochromate also eluted judged by dark color. Redissolved in DCM,washed with sat. NaHCO₃, dried DCM with MgSO₄, filtered and concentratedin vacuo. Purified on a silica gel column using an automated ISCO systemwith gradient of 50-100% EtOAc in hexanes over 30 minutes, then 100%EtOAc for 10 minutes. Combined and concentrated pure fractions,redissolved in acetonltrile and lyophilized to yield title compound.(0.12 g, 15%)

EXAMPLE 23 (2R,4S)-4-Fluoro-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]-2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

Step 1: (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester

Cis-4-hydroxy-D-proline (15 g, 114 mmol) was dissolved In 150 mL ofTHF/H₂O (2:1), added 2M aqueous NaOH solution (86 mL, 172 mmol),followed by Boc₂O (27 g, 126 mmol). Reaction was stirred at ambienttemperature overnight. The solution was acidified with 10% citric acidthen extracted with EtOAc (2×250 mL), washed with water, brine, driedorganics with MgSO₄, filtered and concentrated to yield title compound.(16 g, 61%) APCI (AP−): 230.1 (M−H)⁻.

Step 2:(2R,4R)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester(16 g, 69 mmol) was dissolved in 100 mL DMF, added imidazole (12 g, 173mmol), dimethylaminopyridine (0.85 g, 6.9 mmol), andtert-butyldimethylsilyl chloride (12.5 g, 83 mmol). Stirred at ambienttemperature overnight, dissolved in 350 mL EtOAc, washed with 10% citricacid (3×200 mL), water (2×200 mL), brine, dried with MgSO₄, filtered,and concentrated to yield title compound. (20 g, 84%) APCI (AP−): 344.2(M−H)⁻.

Step 3:(2R,4R)-2-(4-bromo-2-fluoro-phenylcarbamoyl)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester

(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester (4.45 g, 12.9 mmol) was dissolved in 50 mL dryCHCl₃ under an Ar atmosphere, added 4-bromo-2-fluoroaniline (2.45 g,12.9 mmol), EEDQ (3.8 g, 15 mmol), and triethylamine (2.6 mL, 19.3mmol). Reaction was refluxed for 6 hours, cooled and concentrated.Redissolved in EtOAc (250 mL), washed with 10% HCl (2×200 mL), 0.1M NaOH(2×200 mL), water, brine, dried with MgSO₄, filtered and concentrated toyield title compound. (5.5 g, 82%) APCI (AP−): 515.1, 517.1 (M−H)⁻.

Step 4:(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

(2R,4R)-2-(4-Bromo-2-fluoro-phenylcarbamoyl)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester (5.7 g, 10 mmol), 2-(methylthio)benzene boronicacid (2.1 g, 12.6 mmol), and tetrabutylammonium bromide (0.17 g, 0.52mmol) were combined in 50 mL toluene, added 10 mL of a 2M aqueous Na₂CO₃solution followed by tetrakistriphenylphosphine palladium(0) (0.61 g,0.52 mmol). Heated reaction at reflux for 4 hours, cooled, dissolved inEtOAc (250 mL), washed with water (200 mL), brine, dried with MgSO₄,filtered, and concentrated in the presence of 15 g coarse silica.Slurried silica in mobile phase and loaded onto a silica gel column,eluted with 25% EtOAc in hexanes. Combined and concentrated fractions toyield title compound. (4.1 g, 70%) APCI (AP−): 559.3 (M−H)⁻.

Step 5:(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (4.1 g, 7.3 mmol) was dissolved in 20 mL EtOAc,added added m-chloroperoxybenzoic acid (7.2 g, 29 mmol) in one portionand stirred at ambient temperature for 3 hours. A 10% aqueous solution(50 mL) of Na₂S₂O₃ was added to the vigorously stirring reaction inorder to quench peroxide. After 20 minutes the solution was diluted with100 mL EtOAc, separated layers, washed organics with sat. NaHCO₃ (3×100mL), water (2×100 mL), brine, dried with MgSO₄, filtered andconcentrated to yield title compound. (4.3 g, 99%) APCI (AP−): 591.3(M−H)⁻.

Step 6: (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (3.25 g, 5.5 mmol) was dissolved in 50 mL DCM,added 25 mL trifluoroacetic acid and stirred reaction at ambienttemperature for 90 minutes. Solution was concentrated. The resulting oilwas dissolved in 75 mL THF, added triethylamine (3.8 mL, 5.4 mmol)followed by 4-chlorophenylisocyanate (0.84 g, 5.5 mmol). Stirred atambient temperature for 2 hours. The reaction was concentrated andpurified on a silica gel column eluted with straight ethyl acetateinitially moving to 5% MeOH in ethyl acetate. Combined and concentratedpure fractions to yield title compound. (2.5 g, 85%) APCI (AP−): 530.1,532.1(M−H)⁻.

Step 7: (2R,4S)-4-Fluoro-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]-2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

(2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide](0.1 g, 0.19 mmol) in 3 mL dry DCM was added to a solution of[Bis(2-methoxyethyl)amino]-sulfur trifluoride (38 μl, 0.21 mmol) in 3 mLdry DCM at −78° C. under Argon. Stirred at −78° C. for 30 minutes thenallowed to warm to room temperature. Stirred for one hour thenconcentrated reaction. Purified by preparatory HPLC, combined andlyophilized fractions to yield title compound. (0.020 g, 20%) APCI(AP−): 532.1, 534.1(M−H)⁻.

EXAMPLE 24 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]1-p-tolylamide

Step 1: (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester

Cis-4-hydroxy-D-proline (15 g, 114 mmol) was dissolved In 150 mL ofTHF/H₂O (2:1), added 2M aqueous NaOH solution (86 mL, 172 mmol),followed by Boc₂O (27 g, 126 mmol). Reaction was stirred at ambienttemperature overnight. The solution was acidified with 10% citric acidthen extracted with EtOAc (2×250 mL), washed with water, brine, driedorganics with MgSO₄, filtered and concentrated to yield title compound.(16 g, 61%) APCI (AP−): 230.1 (M−H)⁻.

Step 2:(2R,4R)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester(16 g, 69 mmol) was dissolved in 100 mL DMF, added imidazole (12 g, 173mmol), dimethylaminopyridine (0.85 g, 6.9 mmol), andtert-butyldimethylsilyl chloride (12.5 g, 83 mmol). Stirred at ambienttemperature overnight, dissolved in 350 mL EtOAc, washed with 10% citricacid (3×200 mL), water (2×200 mL), brine, dried with MgSO₄, filtered,and concentrated to yield title compound. (20 g, 84%) APCI (AP−): 344.2(M−H)⁻.

Step 3:(2R,4R)-2-(4-bromo-2-fluoro-phenylcarbamoyl)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester

(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester (4.45 g, 12.9 mmol) was dissolved in 50 mL dryCHCl₃ under an Ar atmosphere, added 4-bromo-2-fluoroaniline (2.45 g,12.9 mmol), EEDQ (3.8 g, 15 mmol), and triethylamine (2.6 mL, 19.3mmol). Reaction was refluxed for 6 hours, cooled and concentrated.Redissolved in EtOAc (250 mL), washed with 10% HCl (2×200 mL), 0. 1 MNaOH (2×200 mL), water, brine, dried with MgSO₄, filtered andconcentrated to yield title compound. (5.5 g, 82%) APCI (AP−): 515.1,517.1 (M−H)⁻.

Step 4:(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

(2R,4R)-2-(4-Bromo-2-fluoro-phenylcarbamoyl)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester (5.7 g, 10 mmol), 2-(methylthio)benzene boronicacid (2.1 g, 12.6 mmol), and tetrabutylammonium bromide (0.17 g, 0.52mmol) were combined in 50 mL toluene, added 10 mL of a 2M aqueous Na2CO3solution followed by tetrakistriphenylphosphine palladium(0) (0.61 g,0.52 mmol). Heated reaction at reflux for 4 hours, cooled, dissolved inEtOAc (250 mL), washed with water (200 mL), brine, dried with MgSO₄,filtered, and concentrated in the presence of 15 g coarse silica.Slurried silica in mobile phase and loaded onto a silica gel column,eluted with 25% EtOAc in hexanes. Combined and concentrated fractions toyield title compound. (4.1 g, 70%) APCI (AP−): 559.3 (M−H)⁻.

Step 5:(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (4.1 g, 7.3 mmol) was dissolved in 20 mL EtOAc,added added m-chloroperoxybenzoic acid (7.2 g, 29 mmol) in one portionand stirred at ambient temperature for 3 hours. A 10% aqueous solution(50 mL) of Na₂S₂O₃ was added to the vigorously stirring reaction inorder to quench peroxide. After 20 minutes the solution was diluted with100 mL EtOAc, separated layers, washed organics with sat. NaHCO₃ (3×100mL), water (2×100 mL), brine, dried with MgSO₄, filtered andconcentrated to yield title compound. (4.3 g, 99%) APCI (AP−): 591.3(M−H)⁻.

Step 6: (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]1-p-tolylamide

(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.35 g, 0.59 mmol) was dissolved in 10 mL DCM,added 5 mL trifluoroacetic acid and stirred reaction at ambienttemperature for 2 hours. Solution was concentrated. The resulting oilwas dissolved in 20 mL THF, added triethylamine (0.41 mL, 3 mmol)followed by p-tolylisocyanate (0.079 g, 0.59 mmol). Stirred at ambienttemperature for 2 hours. The reaction was concentrated and purified on asilica gel column eluted using an automated ISCO system with gradient of0-10% MeOH in ethyl acetate over 40 minutes. Concentrated fractions thenredissolved in acetonitrile/water and lyophilized to yield titlecompound. (0.17 g, 56%) APCI (AP−): 510.1(M−H)⁻.

EXAMPLE 25 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]1-[(4-fluoro-phenyl)-amide]

Step 1: (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester

Cis-4-hydroxy-D-proline (15 g, 114 mmol) was dissolved In 150 mL ofTHF/H₂O (2:1), added 2M aqueous NaOH solution (86 mL, 172 mmol),followed by Boc₂O (27 g, 126 mmol). Reaction was stirred at ambienttemperature overnight. The solution was acidified with 10% citric acidthen extracted with EtOAc (2×250 mL), washed with water, brine, driedorganics with MgSO₄, filtered and concentrated to yield title compound.(16 g, 61%) APCI (AP−): 230.1 (M−H)⁻.

Step 2:(2R,4R)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester(16 g, 69 mmol) was dissolved in 100 mL DMF, added imidazole (12 g, 173mmol), dimethylaminopyridine (0.85 g, 6.9 mmol), andtert-butyldimethylsilyl chloride (12.5 g, 83 mmol). Stirred at ambienttemperature overnight, dissolved in 350 mL EtOAc, washed with 10% citricacid (3×200 mL), water (2×200 mL), brine, dried with MgSO₄, filtered,and concentrated to yield title compound. (20 g, 84%) APCI (AP−): 344.2(M−H)⁻.

Step 3:(2R,4R)-2-(4-bromo-2-fluoro-phenylcarbamoyl)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester

(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester (4.45 g, 12.9 mmol) was dissolved in 50 mL dryCHCl₃ under an Ar atmosphere, added 4-bromo-2-fluoroaniline (2.45 g,12.9 mmol), EEDQ (3.8 g, 15 mmol), and triethylamine (2.6 mL, 19.3mmol). Reaction was refluxed for 6 hours, cooled and concentrated.Redissolved in EtOAc (250 mL), washed with 10% HCl (2×200 mL), 0.1M NaOH(2×200 mL), water, brine, dried with MgSO₄, filtered and concentrated toyield title compound. (5.5 g, 82%) APCI (AP−): 515.1, 517.1 (M−H)⁻.

Step 4:(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

(2R,4R)-2-(4-Bromo-2-fluoro-phenylcarbamoyl)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester (5.7 g, 10 mmol), 2-(methylthio)benzene boronicacid (2.1 g, 12.6 mmol), and tetrabutylammonium bromide (0.17 g, 0.52mmol) were combined in 50 mL toluene, added 10 mL of a 2M aqueous Na₂CO₃solution followed by tetrakistriphenylphosphine palladium(0) (0.61 g,0.52 mmol). Heated reaction at reflux for 4 hours, cooled, dissolved inEtOAc (250 mL), washed with water (200 mL), brine, dried with MgSO₄,filtered, and concentrated in the presence of 15 g coarse silica.Slurried silica in mobile phase and loaded onto a silica gel column,eluted with 25% EtOAc in hexanes. Combined and concentrated fractions toyield title compound. (4.1 g, 70%) APCI (AP−): 559.3 (M−H)⁻.

Step 5:(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (4.1 g, 7.3 mmol) was dissolved in 20 mL EtOAc,added added m-chloroperoxybenzoic acid (7.2 g, 29 mmol) in one portionand stirred at ambient temperature for 3 hours. A 10% aqueous solution(50 mL) of Na₂S₂O₃ was added to the vigorously stirring reaction inorder to quench peroxide. After 20 minutes the solution was diluted with100 mL EtOAc, separated layers, washed organics with sat. NaHCO₃ (3×100mL), water (2×100 mL), brine, dried with MgSO₄, filtered andconcentrated to yield title compound. (4.3 g, 99%) APCI (AP−): 591.3(M−H)⁻.

Step 6: (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]1-[(4-fluoro-phenyl)-amide]

(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.35 g, 0.59 mmol) was dissolved in 10 mL DCM,added 5 mL trifluoroacetic acid and stirred reaction at ambienttemperature for 2 hours. Solution was concentrated. The resulting oilwas dissolved in 20 mL THF, added triethylamine (0.41 mL, 3 mmol)followed by 4-fluorophenylisocyanate (0.081 g, 0.59 mmol). Stirred atambient temperature for 2 hours. The reaction was concentrated andpurified on a silica gel column eluted using an automated ISCO systemwith gradient of 80-100% ethyl acetate in hexanes for 20 minutes thenstraight ethyl acetate for 20 minutes. Concentrated fractions thenredissolved in acetonitrile/water and lyophilized to yield titlecompound. (0. 175 g, 57%) APCI (AP−): 514.1 (M−H)⁻.

EXAMPLE 26 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

Step 1: (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester

Cis-4-hydroxy-D-proline (15 g, 114 mmol) was dissolved In 150 mL ofTHF/H₂O (2:1), added 2M aqueous NaOH solution (86 mL, 172 mmol),followed by Boc₂O (27 g, 126 mmol). Reaction was stirred at ambienttemperature overnight. The solution was acidified with 10% citric acidthen extracted with EtOAc (2×250 mL), washed with water, brine, driedorganics with MgSO₄, filtered and concentrated to yield title compound.(16 g, 61%) APCI (AP−): 230.1 (M−H)⁻.

Step 2:(2R,4R)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester(16 g, 69 mmol) was dissolved in 100 mL DMF, added imidazole (12 g, 173mmol), dimethylaminopyridine (0.85 g, 6.9 mmol), andtert-butyldimethylsilyl chloride (12.5 g, 83 mmol). Stirred at ambienttemperature overnight, dissolved in 350 mL EtOAc, washed with 10% citricacid (3×200 mL), water (2×200 mL), brine, dried with MgSO₄, filtered,and concentrated to yield title compound. (20 g, 84%) APCI (AP−): 344.2(M−H)⁻.

Step 3:(2R,4R)-2-(4-bromo-2-fluoro-phenylcarbamoyl)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester

(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester (4.45 g, 12.9 mmol) was dissolved in 50 mL dryCHCl₃ under an Ar atmosphere, added 4-bromo-2-fluoroaniline (2.45 g,12.9 mmol), EEDQ (3.8 g, 15 mmol), and triethylamine (2.6 mL, 19.3mmol). Reaction was refluxed for 6 hours, cooled and concentrated.Redissolved in EtOAc (250 mL), washed with 10% HCl (2×200 mL), 0.1M NaOH(2×200 mL), water, brine, dried with MgSO₄, filtered and concentrated toyield title compound. (5.5 g, 82%) APCI (AP−): 515.1, 517.1 (M−H)⁻.

Step 4:(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

(2R,4R)-2-(4-Bromo-2-fluoro-phenylcarbamoyl)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1-carboxylicacid tert-butyl ester (5.7 g, 10 mmol), 2-(methylthio)benzene boronicacid (2.1 g, 12.6 mmol), and tetrabutylammonium bromide (0.17 g, 0.52mmol) were combined in 50 mL toluene, added 10 mL of a 2M aqueous Na2CO3solution followed by tetrakistriphenylphosphine palladium(0) (0.61 g,0.52 mmol). Heated reaction at reflux for 4 hours, cooled, dissolved inEtOAc (250 mL), washed with water (200 mL), brine, dried with MgSO₄,filtered, and concentrated in the presence of 15 g coarse silica.Slurried silica in mobile phase and loaded onto a silica gel column,eluted with 25% EtOAc in hexanes. Combined and concentrated fractions toyield title compound. (4.1 g, 70%) APCI (AP−): 559.3 (M−H)⁻.

Step 5:(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (4.1 g, 7.3 mmol) was dissolved in 20 mL EtOAc,added added m-chloroperoxybenzoic acid (7.2 g, 29 mmol) in one portionand stirred at ambient temperature for 3 hours. A 10% aqueous solution(50 mL) of Na₂S₂O₃ was added to the vigorously stirring reaction inorder to quench peroxide. After 20 minutes the solution was diluted with100 mL EtOAc, separated layers, washed organics with sat. NaHCO₃ (3×100mL), water (2×100 mL), brine, dried with MgSO₄, filtered andconcentrated to yield title compound. (4.3 g, 99%) APCI (AP−): 591.3(M−H)⁻.

Step 6: (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.35 g, 0.59 mmol) was dissolved in 10 mL DCM,added 5 mL trifluoroacetic acid and stirred reaction at ambienttemperature for 2 hours. Solution was concentrated. The resulting oilwas dissolved in 15 mL DMF, added triethylamine (0.41 mL, 3 mmol)followed by (5-Chloro-pyridin-2-yl)-carbamic acid 4-nitro-phenyl ester(0.17 g, 0.0.59 mmol; see Example 3, step 3a). Stirred at 50° C. for 2hours. The reaction was cooled, dissolved in 100 mL ethyl acetate,washed with sat. NaHCO₃ (3×50 mL), 10% citric acid (2×50 mL), brine,dried with MgSO₄, filtered and concentrated. Purified on a silica gelcolumn eluted using an automated ISCO system with gradient of 0-10% MeOHin ethyl acetate over 40 minutes. Concentrated fractions thenredissolved in acetonitrile/water and lyophilized to yield titlecompound. (0.20 g, 64%) APCI (AP−): 531.1, 533.0(M−H)⁻.

EXAMPLE 27 Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfonyl-3-trifluoromethyl-biphenyl-4-yl)-amide]

Step 1: Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester

DL-proline (10 g, 86.9 mmol) was dissolved in 120 mL of THF: H₂O (2:1),added 87 mL of a 2M NaOH solution followed by Boc₂O (24.6 g, 113 mmol).Stirred at ambient temperature overnight. Removed THF in vacuo,acidified water to pH 3 with citric acid, extracted twice with EtOAc,washed organics with water, brine, dried with MgSO₄, filtered andconcentrated to yield title compound as a white solid. (18.7 g, quant.)APCI (AP−): 214.1 (M−H)⁻.

Step 2:2-(4-Bromo-2-trifluoromethyl-phenylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (4 g, 18.6 mmol)was dissolved in 200 mL dry diethyl ether under Ar, cooled in an icewater bath, added dry pyridine (9 mL, 111 mmol) followed by the dropwiseaddition of oxalyl chloride (4.8 mL, 54 mmol). A precipitate formsimmediately. The reaction was stirred vigorously at 0° C. for one hour,then at ambient temperature for one hour. Added 100 mL diethyl ether,filtered off solids washing with diethyl ether. Concentrated thefiltrates to an off white oil. Redissolved (2 g, 8.5 mmol) oil in 40 mLdry DCM under Ar, cooled to 0° C., added 2.8 mL pyridine followed by4-bromo-2-trifluoromethylaniline (2.05 g, 8.6 mmol). The reaction wasallowed to warm to ambient temperature, stirred overnight thenconcentrated. Redissolved in 100 mL EtOAc, washed with 1 N HCl (3×50mL), brine (100 mL), dried with MgSO₄, filtered and concentrated toyield title compound. (1.98 g, 53%) APCI (AP−): 435.0, 437.0 (M−H)⁻.

Step 3:2-(2′-Methylsulfanyl-3-trifluoromethyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

2-(4-Bromo-2-trifluoromethyl-phenylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (1.92 g, 4.4 mmol), 2-(methylthio)benzene boronicacid (0.88 g, 5.2 mmol), and tetrabutylammonium bromide (70 mg, 0.22mmol) were combined in 40 mL toluene, added 4.4 mL of a 2M aqueousNa2CO₃ solution followed by tetrakistriphenylphosphine palladium(0)(0.253 g, 0.22 mmol). Heated reaction at reflux 4 hours, cooled,concentrated, redissolved in EtOAc (250 mL), washed with water (3×200mL), brine (200 mL), dried with MgSO₄, filtered, and concentrated.Purified on a silica gel column eluted with 20% EtOAc in hexanes.Combined and concentrated pure fractions to yield title compound. (1.8g, 85%) APCI (AP−): 479.1 (M−H)⁻.

Step 4:2-(2′-Methanesulfonyl-3-trifluoromethyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

2-(2′-Methylsulfanyl-3-trifluoromethyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (1.8 g, 3.7 mmol) was dissolved in 20 mLacetonitrile, and added oxone (4.6 g, 6.8 mmol) in one portion andstirred at ambient temperature 4 days and then concentrated. Redissolvedin 100 mL EtOAc and 100 mL sat. NaHCO₃, separated layers, washedorganics with brine, dried with MgSO₄, filtered and concentrated.Purified on a silica gel column eluted with 20% EtOAc in hexanes.Combined and concentrated pure fractions to yield title compound. (1.05g, 55%) APCI (AP−): 511.1 (M−H)⁻.

Step 5: Pyrrolidine-2-carboxylic acid(2′-methanesulfonyl-3-trifluoromethyl-biphenyl-4-yl)-amide

2-(2′-Methanesulfonyl-3-trifluoromethyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.97 g, 1.9 mmol) was dissolved in 10 mL DCM and5 mL trifluoroacetic acid and stirred at ambient temperature overnightand concentrated. Redissolved in 100 mL EtOAc and 100 mL sat. NaHCO₃,separated layers, washed organics with brine, dried with MgSO₄, filteredand concentrated to yield title compound as an oil (0.78 g, 100%) APCI(AP−): 411.0 (M−H)⁻.

Step 6: Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfonyl-3-trifluoromethyl-biphenyl-4-yl)-amide]

Pyrrolidine-2-carboxylic acid(2′-methanesulfonyl-3-trifluoromethyl-biphenyl-4-yl)-amide (0.4 g, 0.97mmol) was dissolved in 10 mL THF, added diisopropylethylamine (0.5 mL,2.9 mmol), followed by 4-chlorophenylisocyanate (148 mg, 0.96 mmol).Stirred reaction at ambient temperature for one hour then concentrated.Purified on a silica gel column eluted with 20% moving to 50% EtOAc inhexanes. Combined and concentrated pure fractions to yield titlecompound. (0.48 g, 88%) APCI (AP−): 564.0, 566.0 (M−H)⁻.General Procedure for Preparation of Examples 28n et. seq.:

Synthesis of 2 (Step 1): As provided in Route 1, a mixture of 1 (wherethe structure of YAZ is as provided in the Scheme), B (where B is anitrogen in a heteroaryl or heterocyloalkly ring, an acyclic alkylprimary or secondary amine, or an acyclic primary or secondary amide),K₃PO₄, CuI, and trans-diaminocyclohexane is heated in dioxane at refluxto obtain compound 2, wherein the point of attachment of YA to B is thenitrogen of the heteroaryl or heterocyloalkly ring, or the nitrogen ofthe acyclic primary or secondary alkyl amine, or the nitrogen of theacyclic primary or secondary amide. In the case where Y is a nitrogroup, the moiety is reduced to the amino group with RaNi and EtOH undera hydrogen atmosphere.

Alternatively, as provided in Route 2, CuI, K₂CO₃, and8-hydroxyquinoline in DMSO can be used to carry out the couplingreaction.

Synthesis of 4 (Step 2): The appropriate aniline (2=YAB),N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), triethylamine andcarboxylic acid (3) are heated at reflux in chloroform to produce 4.

Synthesis of 5: A solution of compound 4, TFA and DCM is stirred at roomtemperature for 1h and then concentrated under reduced pressure. Theresulting oil is dissolved in THF and cooled to 0° C. followed by theaddition of triethylamine and the appropriate isocyanate to producecompound 5.

EXAMPLE 28 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}

Step 1: (2R,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid methyl ester

Cis-4-Hydroxy-D-proline (15 g, 115 mmol) was suspended in 150 mLanhydrous methanol under an argon atmosphere, then cooled to 0° C.before bubbling in HCl gas for 15 minutes. The solution gradually becamehomogenous. The argon and HCl gas lines were removed and the solutionwas refluxed for 4 h. The solution was cooled and then concentratedunder reduced pressure. The crude material was redissolved in 100 mLmethanol and diethyl ether was added until a precipitate formed. Theprecipitate was filtered off, washed with diethyl ether, and dried invacuo overnight to reveal 1 (20 g, 95%) as a white solid. MS: APCI(AP+): 146 (M)+.

Step 2: (2R,4R)-4-Hydroxy-1-trityl-pyrrolidine-2-carboxylic acid methylester (2)

Into a solution of 1 (10 g, 55 mmol) in anhydrous CHCl₃ (100 mL) wasadded triethylamine (19 mL, 138 mmol) and triphenylmethyl chloride (14.5g, 52 mmol). The mixture was stirred at RT for 3d before concentratingand redissolving in EtOAc. The solution was washed sequentially with 10%aq. citric acid, water, and brine before drying over MgSO₄ andconcentrating under reduced pressure to reveal 2 (20 g, 100%) as ayellow solid.

Step 3: (2R,4R)-4-Methoxy-1-trityl-pyrrolidine-2-carboxylic acid methylester (3)

Into a solution of 2 (5.71 g, 14.7 mmol) in anhydrous DMF (20 mL) andanhydrous THF (20 mL) was added Mel (3.67 mL, 58.9 mmol). The solutionwas cooled to 0° C. in an ice bath and NaH (0.766 g, 19.2 mmol) wasadded in one portion. The mixture was stirred at RT for 26 h beforeadding EtOAc and washing sequentially with water and brine. The organiclayer was dried over MgSO₄ and concentrated under reduced pressure.Purification of the crude material by flash chromatography revealed 3(4.67 g, 79%) as a white solid.

Step 4: (2R,4R)-4-Methoxy-pyrrolidine-2-carboxylic acid methyl ester (4)

To a flask containing 3 (4.67 g, 11.6 mmol) was added a solution ofCH₂Cl₂ (27 mL), water (0.3 mL), and TFA (3.0 mL, 38.9 mmol). Thesolution was stirred at RT for 3 h before concentrating under reducedpressure to reveal impure 4. MS: APCI (AP+): 160.1 (M)+.

Step 5: (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester 2-methyl ester (5)

Into a solution of 4 (1.85 g, 11.6 mmol) in CH₂Cl₂ (20 mL) was addedtriethylamine (6.49 mL, 46.5 mmol), di-tert-butyl dicarbonate (5.08 g,23.3 mmol), and dimethylaminopyridine (0.142 g, 1.16 mmol). The mixturewas stirred at RT for 22 h before concentrating under reduced pressureand redissolving in EtOAc. The solution was washed sequentially with 10%aq. citric acid and brine before drying over MgSO₄ and concentratingunder reduced pressure. The crude material was purified by flashchromatography to reveal 5 (2.54 g, 84% over two steps) as a yellowsolid. MS: APCI (AP+): 260.1 (M)+.

Step 6: (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester (6)

Into a solution of 5 (2.54 g, 9.80 mmol) in acetonitrile (20 mL) wasadded water (20 mL) and LiOH H₂O (1.64 g, 39.2 mmol). The mixture wasstirred at RT for 28 h before removing the acetonitrile under reducedpressure. EtOAc was added to the residue that was then washed with 1NHCl. The aqueous layer was extracted with additional EtOAc and thecombined organic layers were washed with brine and dried over MgSO₄. Thesolution was concentrated under reduced pressure to reveal 6 (2.16 g,90%) as a white solid. MS: APCI (AP−): 244.1 (M)−.

Step 7: 1-(4-Amino-3-fluoro-phenyl)-piperidin-2-one (7)

2-Fluoro-4-iodoaniline (10.0 g, 42.2 mmol) was combined withδ-valerolactam (6.27 g, 63.3 mmol), CuI (0.804 g, 4.22 mmol), and K₃PO₄(22.4 g, 105 mmol). 1,4-Dioxane (60 mL) was added followed bytrans-1,2-diaminocyclohexane (1.01 mL, 8.44 mmol). The mixture washeated to reflux for 22 h before cooling and diluting with EtOAc. Themixture was filtered through a plug of silica, eluting with EtOAc, andthe filtrate concentrated under reduced pressure. Purification of thecrude product by flash chromatography revealed 7 (3.40 g, 39%) as abrown solid. MS: APCI (AP+): 209.1 (M)+.

Step 8:(2R,4R)-2-[2-Fluoro-4-(2-oxo-piperidin-1-yl)-phenylcarbamoyl]-4-methoxy-pyrrolidine-1-carboxylicacid tert-butyl ester (8)

Into a solution of 6 (0.250 g, 1.02 mmol) in CHCl₃ (10 mL) was added 7(0.212 g, 1.02 mmol), EEDQ (0.302 g, 1.22 mmol), and triethylamine(0.213 mL, 1.53 mmol). The solution was stirred at reflux for 19 hbefore cooling to RT and adding EtOAc. The solution was washedsequentially with 10% aq. citric acid, 1N NaOH, water, and brine, beforedrying over MgSO₄ and concentrating under reduced pressure. The crudematerial was purified by flash chromatography to reveal 8 (0.329 g, 74%)as a tan foam. MS: APCI (AP+): 436.1 (M)+, (AP−): 434.1 (M)−.

Step 9: (2R, 4R)-4-Methoxy-pyrrolidine-2-carboxylic acid[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide (9)

Into a solution of 8 (0.329 g, 0.761 mmol) in anhydrous CH₂Cl₂ (5 mL)was added TFA (5 mL). The solution was stirred at RT for 0.5 h beforeconcentrating under reduced pressure to reveal 9 (0.255 g, 100%) as atan oil.

Step 10: (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}(10)

Into a solution of 9 (0.128 g, 0.380 mmol) in anhydrous THF (5 mL) at 0°C. was added triethylamine (0.265 mL, 1.90 mmol) and 4-chlorophenylisocyanate (0.058 g, 0.380 mmol). The solution was stirred at RT for 3.5h before concentrating under reduced pressure. The crude material waspurified by flash chromatography, followed by filtration through afritted funnel and concentration under reduced pressure. Remaining EtOAcwas azeotroped off with CHCl₃. The resulting solid was lyophilized fromacetonitrile/water to reveal 10 (0.186 g, 100%) as a white solid. MS:APCI (AP+): 489.1 (M)+, (AP−): 487.1 (M)−; CHN calc'd forC₂₄H₂₆Cl₁F₁N₄O₄: % C 50.75; % H 4.58; % N 9.07. Found: % C 50.62; % H4.19; % N 9.02.

EXAMPLE 29 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2-oxo-piperidin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided in Example 28. MS: APCI(AP+): 457.1 (M)+.

EXAMPLE 30 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided in Example 28. MS: APCI(AP+): 475.1 (M)+.

EXAMPLE 31 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided in Example 28. MS: APCI(AP+): 476.1 (M)+.

EXAMPLE 32 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided in Example 28. MS: APCI(AP+): 490.1 (M)+.

EXAMPLE 33 (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided in Example 28. MS: APCI(AP+): 504.1 (M)+.

EXAMPLE 34 (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided in Example 28. MS: APCI(AP+): 503.1 (M)+.

EXAMPLE 35 (2R,4R)-4-Propoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided in Example 28. MS: APCI(AP+): 517.2 (M)+.

EXAMPLE 36 (2R,4R)-4-Propoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided in Example 28. MS: APCI(AP+): 518.2 (M)+.

EXAMPLE 37 (2R,4R)-4-Cyano-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided in Example 28. MS: APCI(AP+): 484.2 (M)+.

EXAMPLE 38 (2R,4R)-4-Fluoro-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided in Example 28. MS: APCI(AP+): 477.1 (M)+.

EXAMPLE 39 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-azetidin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided in Example 28. MS: APCI(AP+): 461.1 (M)+.

EXAMPLE 40 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-azetidin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided in Example 28. MS: APCI(AP+): 462.1 (M)+.

EXAMPLE 41 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided in Example 28. MS: APCI(AP+): 475.2 (M)+.

EXAMPLE 42 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-pyrrolidin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided in Example 28. MS: APCI(AP+): 476.2 (M)+.

EXAMPLE 43 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-azepan-1-yl)-phenyl]-amide}

The compound was prepared as generally provided in Example 28. MS: APCI(AP+): 503.2 (M)+.

EXAMPLE 44 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-azepan-1-yl)-phenyl]-amide}

The compound was prepared as generally provided in Example 28. MS: APCI(AP+): 504.2 (M)+.

EXAMPLE 45 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided in Example 28. MS: APCI(AP+): 468.2 (M)+.

EXAMPLE 46 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided in Example 28. MS: APCI(AP+): 467.2 (M)+.

EXAMPLE 47 (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided in Example 28. MS: APCI(AP+): 499.2 (M)+.

EXAMPLE 48 (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided in Example 28. MS: APCI(AP+): 500.2 (M)+.

EXAMPLE 49 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-hydroxymethyl-5-oxo-pyrrolidin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided in Example 28. MS: APCI(AP+): 505.2 (M)+.

EXAMPLE 50 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2,3-dimethyl-5-oxo-2,5-dihydro-pyrazol-1-yl)-phenyl]-amide}

The compound was prepared as generally provided in Example 28. MS: APCI(AP+): 470.2 (M)+.

EXAMPLE 51 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2-hydroxymethyl-pyrrolidin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided in Example 28. APCI(AP+): 459.2 (M+H)+.

EXAMPLE 52 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-pyrrolidin-1-yl-phenyl)-amide]

The compound was prepared as generally provided in Example 28. APCI(AP+): 429.1 (M)+.

EXAMPLE 53 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-pyrazol-1-yl-phenyl)-amide]

The compound was prepared as generally provided in Example 28. APCI(AP+): 426.1 (M)+.

EXAMPLE 54 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-fluoro-4-pyrazol-1-yl-phenyl)-amide]

The compound was prepared as generally provided in Example 28. APCI(AP+): 444.1 (M)+.

EXAMPLE 55 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-[1,2,4]triazol-1-yl-phenl)-amide]

The compound was prepared as generally provided in Example 28. APCI(AP+): 427.1 (M)+.

EXAMPLE 56 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-[1,2,3]triazol-2-yl-phenyl)-amide]

The compound was prepared as generally provided in Example 28. APCI(AP+): 427.1 (M)+.

EXAMPLE 57 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-[1,2,3]triazol-1-yl-phenyl)-amide]

The compound was prepared as generally provided in Example 28. APCI(AP+): 427.1 (M)+.

EXAMPLE 58 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid2-[(4-acetylamino-phenyl)-amide]1-[(4-chloro-phenyl)-amide]

The compound was prepared as generally provided in Example 28. APCI(AP+): 417.1 (M)+.

EXAMPLE 59 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(cyclopentanecarbonyl-amino)-phenyl]-amide}

The compound was prepared as generally provided in Example 28. APCI(AP+): 471.2 (M)+.

EXAMPLE 60 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-pyrimidin-5-yl-phenyl)-amide]

The compound was prepared as generally provided in Example 28. APCI(AP+): 484.2 (M)+.

EXAMPLE 61 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-pyrazol-1-yl-phenyl)-amide]

The compound was prepared as generally provided in Example 28. APCI(AP+): 440.2 (M)+.

EXAMPLE 62 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-fluoro-4-pyrazol-1-yl-phenyl)-amide]

The compound was prepared as generally provided in Example 28. APCI(AP+): 458.1 (M)+.

EXAMPLE 63 (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-fluoro-4-pyrazol-1-yl-phenyl-amide]

The compound was prepared as generally provided in Example 28. APCI(AP+): 472.1 (M)+.

EXAMPLE 64 (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-pyrazol-1-yl-phenyl)-amide]

The compound was prepared as generally provided in Example 28. APCI(AP+): 454.2 (M)+.

EXAMPLE 65 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-methyl-pyrazol-1-yl)-phenyl]-amide}

Step 1: 2-Fluro-4-(3-methyl-pyrazol-1-yl)phenylamine (1)

2-Fluoro-4-iodoaniline (3.0 g, 12.6 mmol), 3-methylpyrazole (1.22 mL,15.18 mmol), Cs₂CO₃ (8.66 g, 26.58 mmol) and CuI (0.072 g, 0.379 mmol)were placed in a flask under nitrogen. The flask was evacuated undervacuum and refilled with nitrogen (5 times). 1,4-Dioxane (15 mL) wasadded followed by trans-1,2-diaminocyclohexane (152 μL, 1.266 mmol). Thereaction mixture was heated under reflux for 36 h. Mixture cooled andfiltered. Solvents removed. Residue purified by silica gel flashchromatography eluting with a gradient of EtOAc in hexanes (0 to 30%).This purification afforded 1 as a pale brown solid (0.917 g, 38%). MS:APCI (AP+): 192.0 (M)+.

From the same purification, 2-Fluro-4-(5-methyl-pyrazol-1-yl)phenylamine(2) was obtained as pale brown solid (0.265 g, 11%). MS: APCI (AP+):192.0 (M)+.

Step 2:(2R,4R)-2-[2-Fluoro-4-(3-methyl-pyrazol-1-yl)-phenylcarbamoyl]-4-methoxy-pyrrolidine-1-carboxylicacid tert-butyl ester (3)

(2R,4R)-4-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester(0.350 g, 1.427 mmol), aniline 1 (0.273 g, 1.427 mmol) and EEDQ (0.529g, 2.140 mmol) were dissolved in CHCl₃ (30 mL). Et₃N (0.6 mL, 4.281mmol) was added and the reaction mixture was heated at reflux for 18 h.The mixture was allowed to cool and diluted with CHCl₃ (100 mL) andwashed with 5% HCl, 0.5 N NaOH, water and brine (40 mL each), theorganic extract was dried over MgSO₄, filtered and the solvent removedto give a pale tan foam. The crude product was used for the next stepwithout purification. MS: APCI (AP+): 419.2 (M)+, (AP−): 417.2 (M)−.

Step 3: (2R, 4R)-4-Methoxy-pyrrolidine-2-carboxylic acid[2-fluoro-4-(3-methyl-pyrazol-1-yl)-phenyl]-amide (4)

Boc-amine 3 (˜0.6 g, 1.427 mmol) was dissolved in 25% TFA indichloromethane. The mixture was stirred at ambient temperature for 2 h.The solvents were removed and the residue dried under vacuum to give 4as a tan oil (˜0.450 g).

Step 4: (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(3-methyl-pyrazol-1-yl)-phenyl]-amide}(5)

A solution of amine 4 (˜0.450 g, 1.427 mmol) in dichloromethane (35 mL)was cooled at 0° C. Triethylamine (1.5 mL, 10.7 mmol) was added and themixture stirred for 15 min. Then, 4-chlorophenyl isocyanate (0.24 g,1.569 mmol) was incorporated. The solution was stirred at ambienttemperature for 18 h. The mixture was diluted with CHCl₃ (100 mL) andwashed with 5% HCl, water, brine (40 mL each). The organic extracts weredried over MgSO₄, filtered and the solvent removed. The residue waspurified by flash chromatography on silica gel eluting with a gradientof EtOAc in hexanes (0 to 65%) to provide 5 as white solid (0.56 g, 83%in 3 steps). MS: APCI (AP+): 472.2 (M)+, (AP−): 470.2 (M)−. Anal. calcdfor C₂₃H₂₃ClFN₅O₃: C, 58.54; H, 4.91; N, 14.84. Found: C, 58.35; H,4.59; N, 14.49.

EXAMPLE 66 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(5-methyl-pyrazol-1-yl)-phenyl]-amide}

The compound was prepared as generally provided for Example 65. APCI(AP+): 458.2 (M)+.

EXAMPLE 67 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(5-methyl-pyrazol-1-yl)-phenyl]-amide}

The compound was prepared as generally provided for Example 65. APCI(AP+): 472.2 (M)+.

EXAMPLE 68 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(5-methyl-pyrazol-1-yl)-phenyl]-amide}

The compound was prepared as generally provided for Example 65. APCI(AP+): 454.3 (M)+.

EXAMPLE 69 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3,5-dimethyl-pyrazol-1-yl)-phenyl]-amide}

The compound was prepared as generally provided for Example 65. APCI(AP+): 454.2 (M)+.

EXAMPLE 70 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3,5-dimethyl-pyrazol-1-yl)-phenyl]-amide}

The compound was prepared as generally provided for Example 65. APCI(AP+): 468.2 (M)+.

EXAMPLE 71 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(3,5-dimethyl-pyrazol-1-yl)-2-fluoro-phenyl]-amide}

The compound was prepared as generally provided for Example 65. APCI(AP+): 486.2 (M)+.

EXAMPLE 72 1-(4-Amino-3-fluoro-phenyl)-1H-pyridin-2-one

According to Route 2 for the preparation of YAB as provided in theGeneral Procedure for the Preparation of Examples 28-60,2-Fluoro-4-iodoaniline (10.0 g, 42.2 mmol) was combined with1H-pyridin-2-one (1.0 g, 4.22 mmol), CuI (0.120 g, 0.633 mmol), K₂CO₃(0.641 g, 4.64 mmol), and 8-hydroxyquinoline (0.092 g, 0.633 mmol) inDMSO (3 mL). The mixture was degassed with a stream of argon and thenheated at reflux for 20 h before cooling to ambient temperature. 10% aq.NH₄OH and EtOAc were added, and the mixture was filtered through a plugof layered celite and decolorizing charcoal, eluting with EtOAc. Thefiltrate was concentrated under reduced pressure. Purification of thecrude product by mplc revealed the title compound (0.53 g, 62%) as ayellow solid. MS: APCI (AP+): 205.1 (M)+.

EXAMPLE 73 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid2-[(4-tert-butyl-phenyl)-amide]1-[(4-chloro-phenyl)-amide]

The compound was prepared as generally provided for Example 28. MS: APCI(AP+): 414.2 (M)+.

EXAMPLE 74 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2[(3,5′difluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]

Step 1: N-tert-Butyl-4-fluoro-benzenesulfonamide

Into a DCM solution (50 mL) of tert-butylamine (5.9 mL, 56.5 mmol) andtriethylamine (7.16 mL, 51.3 mmol) at 0° C. was slowly added a DCMsolution (20 mL) of 4-fluoro-benzenesulfonyl chloride (10 g, 51.3 mmol),and the reaction stirred at RT for 19 h. The reaction was concentratedand the resulting solid recrystalized from ether/hexanes to get theproduct (9.5 g, 80%)as white crystals. MS: APCI (AP+): 230.1 (M)+.

Step 2: N-tert-Butyl-4-fluoro-benzenesulfonamide-3-boronic acid

Butyllithium (2.2 M, 4.3 mL, 9.51 mmol) was added drop-wise to a 0° C.solution of N-tert-butyl-4-fluoro-benzenesulfonamide (1.0 g, 4.32 mmol),and the solution stirred for 15 min. at 0° C. and then RT for 1.5 h.Triisopropyl borate (1.19 mL, 5.18 mmol) was added, and the solutionstirred at RT of 2.5 h. The mixture was cooled to 0° C., 10% aq. HCl wasadded slowly, and the reaction was stirred for 1.5 h. The reaction wasthen extracted with EtOAc three times and the organics combined andconcentrated. The resulting oil was dissolved in ether and extractedwith 1N NaOH three times, and the extracts combined and acidified at 0°C. with 6N HCl. The solution was extracted with ether three times andthe organics were combined and dried over MgSO₄. Filtration andconcentration of the organics revealed the product as an oil whichformed a solid upon addition of hexanes and concentration under reducedpressure. (0.641 g, 54%) APCI (AP−): 274.1 (M)−.

Step 3:(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(2-fluoro-4-iodo-phenylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

4-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester (0.673 g, 1.94 mmol), 2-fluoro-4-iodoaniline (0.46 g,1.94 mmol), EEDQ (0.575 g, 2.32 mmol) and triethylamine (0.408 mL, 2.91mmol) were heated at reflux in CHCl₃ (10 mL) for 22 h. The solution wasconcentrated and resulting oil partitioned between EtOAc and water. Theorganic layer was washed with brine and dried over MgSO₄. The productwas purified by mplc to produce the product as a clear oil (1.0 g, 90%).MS: APCI (AP−): 563.2 (M)−.

Step 4:(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(2′-tert-butylsulfamoyl-3,5′-difluoro-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester

A mixture of4-(tert-butyl-dimethyl-silanyloxy)-2-(2-fluoro-4-iodo-phenylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.56 g, 0.99 mol), Pd(PPh₃)₄ (0.11 g, 0.1 mmol),N-tert-butyl-4-fluoro-benzenesulfonamide-3-boronic acid (0.33 g, 1.19mmol), tetrabutylammonium bromide (0.016 g, 0.05 mmol), sodium carbonate(0.210 g, 1.98 mmol), water (2.0 mL) and toluene (10 mL) was degassedwith a stream of argon gas and then heated at reflux 21.5 h. The mixturewas then allowed to cool to RT, concentrated and partitioned betweenwater and EtOAc. The organic layer was washed with brine, dried overMgSO₄ and concentrated. The resulting oil was purified by mplc to revealthe product as an oil (0.119 g, 18%). MS: APCI (AP−): 666.4 (M)−.

Step 5: (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid2-[(2′-tert-butylsulfamoyl-3,5′-difluoro-biphenyl-4-yl)-amide]1-[(4-chloro-phenyl)-amide]

A solution of4-(tert-butyl-dimethyl-silanyloxy)-2-(2′-tert-butylsulfamoyl-3,5′-difluoro-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (0.228 g, 0.342 mmol) and trifluoroacetic acid(1.5 mL) in CHCl₃ (1.5 mL) was stirred at ambient temperature for 1 h.The solution was concentrated, hexanes added and then the solutionconcentrated again. The resulting oil was dissolved in THF and cooled 0°C. Triethylamine (0.190 mL, 1.36 mmol) was added followed by4-chlorophenyl isocyanate (0.052 g, 0.342 mmol) and the solution stirredat RT for 5.5 h. The solution was concentrated and the oil purified bymplc to reveal the product as a solid (0.078 g, 38%). MS: APCI (AP−):605.2 (M)−.

Step 6: (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2[(3,5′difluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]

4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid2-[(2′-tert-butylsulfamoyl-3,5′-difluoro-biphenyl-4-yl)-amide]1-[(4-chloro-phenyl)-amide](0.078 g, 0.128 mmol) was dissolved in TFA (3 mL) and stirred at RT for1 h. The reaction was concentrated and dissolved in MeCN and water andpurified by reverse phase HPLC to reveal the product as a white solid(0.05 g, 77%) after lyophilization. MS: APCI (AP+): 551.1 (M)+.

EXAMPLE 75 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-amide]

The compound was prepared as generally provided for Example 28. MS: APCI(AP+): 472.2 (M)+.

EXAMPLE 75a Alternative Procedure

Synthesis of 2:

A solution of 1 where Y is a nitro group is treated with ahalo-alkoylchloride in the presence of base and refluxing toluene toproduce an intermediate halo-amide that is then cyclized in the presenceof potassium tert-butoxide in THF to produce a cyclic lactam B.

Synthesis of 3:

A solution of 2 where Y is a nitro group is reduced under RaNi mediatedhydrogenation to produce 3 where Y is an amino group.

Synthesis of 5 and 6:

Intermediates 5 and 6 were prepared as provided in Example 28.

EXAMPLE 76 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl)-amide]

Step 1: 5′-Nitro-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

See Example 75a. 2-Amino-5-nitro-pyridine (2.0 g, 14.3 mmol),5-bromo-pentanoyl chloride (2.86 g, 14.3 mmol), triethylamine (2.39 g,17.2 mmol), catalytic DMAP were heated at reflux in toluene (70 mL) 22h. The reaction was allowed to cool to RT, concentrated and theresulting oil portioned between EtOAc and water. The organic layer wasseparated, washed with brine, dried over MgSO₄ and filtered.Concentration of the filtrate produced an oil which was dissolved in THF(140 mL). Potassium tert-Butoxide (1.68 g, 15.0 mmol) was addedportion-wise and the reaction stirred at RT for 2 h. Water was thenadded, and the reaction extracted with EtOAc. The organics were thenwashed with brine and dried over MgSO4. Purification of the crudematerial by mplc revealed the product as an orange solid. MS: APCI(AP+): 222.1 (M)+.

Step 2: 5′-Amino-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one

5′-Nitro-3,4,5,6-tetrahydro-[1,2′]bipyridinyl-2-one (0.66 g, 2.98 mmol)was dissolved in 1:1 MeOH/THF (50 mL) and hydrogenated over RaNi (1 g)at 4285 psi/mole for 0.8 h. The catalyst was filtered, and the filtrateconcentrated. The crude solid was purified by recrystalization from THFand hexanes to give the product as a yellow solid (0.275 g, 48%). MS:APCI (AP+): 192.1 (M)+.

Step 3: (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl)-amide]

The compound was prepared as generally provided for Example 28. MS: APCI(AP+): 472.2 (M)+.

EXAMPLE 77 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(2,3-dimethyl-5-oxo-2,5-dihydro-pyrazol-1-yl)-phenyl]-amide}

The compound was prepared as generally provided for Example 28.Formation of the 5-chloro-pyridin-2-yl moiety can be found in Example26. MS: APCI (AP+): 485.3 (M)+.

EXAMPLE 78 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2,3-dimethyl-5-oxo-2,5-dihydro-pyrazol-1-yl)-phenyl]-amide}

The compound was prepared as generally provided for Example 28. MS: APCI(AP+): 484.3 (M)+.

EXAMPLE 79 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-oxo-2H-[1,3′]bipyridinyl-6′-yl)-amide]

Step 1. 6′-Amino-[1,3′]bipyridinyl-2-one

2-Amino-5-iodopyridine (5.0 g, 22.7 mmol) was combined with1H-pyridin-2-one (2.59 g, 27.27 mmol), CuI (0.65 g, 3.41 mmol), K₂CO₃(3.45 g, 24.9 mmol), and 8-hydroxyquinoline (0.49 g, 3.40 mmol) in DMSO(20 mL). The mixture was degassed with a stream of argon and then heatedat reflux for 18 h before cooling to RT. 10% aq. NH₄OH and EtOAc wereadded, and the mixture was filtered through a plug of layered celite anddecolorizing charcoal, eluting with EtOAc. The filtrate was concentratedunder reduced pressure. Purification of the crude product by mplcrevealed A (0.40 g, 10%) as a yellow solid. MS: APCI (AP+): 188.1 (M)+.

Step 2: (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-oxo-2H-[1,3′]bipyridinyl-6′-yl)-amide]

The compound was prepared as generally provided for Example 28. MS: APCI(AP+): 468.3 (M)+.

EXAMPLE 80 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl)-amide]-TFASalt

The compound was prepared as generally provided in Examples 28 and 75a.Formation of the 5-chloro-pyridin-2-yl moiety can be found in Example26. Purification was accomplished via reverse phase HPLC. MS: APCI(AP+): 473.2 (M)+.

EXAMPLE 81 4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-oxo-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-yl)-amide]

The compound was prepared as generally provided for Example 28. MS: APCI(AP+): 486.3 (M)+.

EXAMPLE 82 (2R,4R)-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-oxo-2H-[1,3′]bipyridinyl-6′-yl)-amide]

The compound was prepared as generally provided for Examples 28 and 79.MS: APCI (AP+): 482.3 (M)+.

EXAMPLE 83 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(6-oxo-6H-pyridazin-1-yl)-phenyl]-amide}

Step 1: 2-(4-Amino-3-fluoro-phenyl)-2H-pyridazin-3-one

2-Fluoro-4-iodoaniline (0.5 g, 2.10 mmol) was combined with2H-Pyridazin-3-one (0.243 g, 2.53 mmol), CuI (0.06 g, 0.315 mmol), K₂CO₃(0.32 g, 2.31 mmol), and 8-hydroxyquinoline (0.046 g, 0.315 mmol) inDMSO (3mL). The mixture was degassed with a stream of argon and thenheated at reflux for 23 h before cooling to RT. 10% aq. NH₄OH and EtOAcwere added, and the mixture was filtered through a plug of layeredcelite and decolorizing charcoal, eluting with EtOAc. The filtrate wasconcentrated under reduced pressure. Purification of the crude productby mplc revealed A (0.16 g, 37%) as a yellow solid. MS: APCI (AP+):206.1 (M)+.

Step 2: (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(6-oxo-6H-pyridazin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided for Example 28. MS: APCI(AP+): 486.1 (M)+.

EXAMPLE 84 (2R,4S)-4-Amino-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

Step 1: (2R,4R)-toluene-4-sulfonic acid1-(4-chloro-phenylcarbamoyl)-5-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidin-3-ylester

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide](see example 17, 0.41 g, 0.77 mmol) was dissolved in 5 ml dry DCM, addedEt3N (0.21 mL, 1.54 mmol), DMAP (10 mg, 0.8 mmol), and TsCl (0.16 g,0.85 mmol). Stirred at ambient temperature overnight. The solution wasdissolved in 100 ml EtOAc, washed with 10% citric acid (3×50 ml), satNaHCO3 (3×50 ml), brine (100 ml), dried with MgSO4, filtered andconcentrated to yield title compound. (0.54 g, 97%) MS: APCI (AP−):684.1 (M)−.

Step 2: (2R,4S)-4-Azido-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

(2R,4R)-toluene-4-sulfonic acid1-(4-chloro-phenylcarbamoyl)-5-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidin-3-ylester (0.2 g, 0.29 mmol) was dissolved in 4 ml dry DMF under Ar, addedsodium azide (0.38 mg, 0.58 mmol) and stirred at 60° C. for 6 hours. Thereaction was cooled, taken up in 100 ml EtOAc, washed with water, sat.NaHCO3, brine, dried with MgSO4, filtered and concentrated to yieldtitle compound. (0.155 g, 95%) MS: APCI (AP+): 557.0 (M)+.

Step 3: (2R,4S)-4-Amino-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

(2R,4S)-4-Azido-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide](0.145 g, 0.26 mmol) was shaken with Raney Nickel (300 mg) in 16 mLtetrahydrofuran in a hydrogen atmosphere under pressure for 3 days.Reaction was filtered and concentrated. Purified by HPLC and lyophilizedpure fractions to yield title compound. (105 mg, 76%) MS: APCI (AP−):529.1 (M)−.

EXAMPLE 85 (2R,4R)-4-Amino-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 85substituting (2R,4S)-toluene-4-sulfonic acid1-(4-chloro-phenylcarbamoyl)-5-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidin-3-yl ester for (2R,4R)-toluene-4-sulfonic acid1-(4-chloro-phenylcarbamoyl)-5-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidin-3-ylester. MS: APCI (AP+): 531.1 (M)+.

EXAMPLE 86 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 17,substituting 2-(N-tert-butyl)phenylsulfonamide boronic acid for2-(methylthio)benzene boronic acid. MS: APCI (AP+): 533.0 (M)+.

EXAMPLE 87 (2R)-4-Hydroxyimino-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 22. MS: APCI(AP+): 545.0 (M)+.

EXAMPLE 88 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methylsulfamoyl-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 86. MS: APCI(AP+): 547.2 (M)+.

EXAMPLE 89 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-dimethylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 86. MS: APCI(AP+): 561.2 (M)+.

EXAMPLE 90 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 28,substituting 3-fluoro-2′-methanesulfonyl-biphenyl-4-ylamine for1-(4-amino-3-fluoro-phenyl)-piperidin-2-one. MS: APCI (AP+): 547.1 (M)+.

EXAMPLE 91 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 28,substituting 4′-amino-3′-fluoro-biphenyl-2-sulfonic acid tert-butylamidefor 1-(4-amino-3-fluoro-phenyl)-piperidin-2-one. MS: APCI (AP+): 549.0(M)+.

EXAMPLE 92 (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 90,substituting (2R,4R)-4-ethoxy-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester for (2R,4R)-4-methoxy-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester. MS: APCI (AP+): 561.1 (M)+.

EXAMPLE 93 (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 28,substituting (2R,4R)-4-ethoxy-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester for (2R,4R)-4-methoxy-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester. MS: APCI (AP+): 560.2 (M)+.

EXAMPLE 94 (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 91,substituting (2R,4R)-4-ethoxy-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester for (2R,4R)-4-methoxy-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester. MS: APCI (AP+): 561.1 (M)+.

EXAMPLE 95 (2R,4S)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 28,substituting (2R,4S)-4-methoxy-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester for (2R,4R)-4-methoxy-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester. MS: APCI (AP+): 546.0 (M)+.

EXAMPLE 96 (2R,4R)-4-Fluoro-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 28,substituting (2R,4R)-4-ethoxy-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester for (2R,4R)-4-methoxy-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester MS: APCI (AP+): 534.0 (M)+.

EXAMPLE 97 (2R)-4,4-Difluoro-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 28,substituting (2R)-4-difluoro-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester for (2R,4R)-4-methoxy-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester. MS: APCI (AP+): 552.0 (M)+.

EXAMPLE 98 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]1-[(4-fluoro-phenyl)-amide]

The compound was prepared as generally provided for Example 28,substituting 4-fluorophenyl isocyanate for 4-chlorophenyl isocyanate.MS: APCI (AP+): 530.2 (M)+.

EXAMPLE 99 (2R,4R)-4-Acetylamino-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 84. MS: APCI(AP+): 573.2 (M)+.

EXAMPLE 100 (2R,4R)-4-Methanesulfonylamino-pyrrolidine-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 84. MS: APCI(AP+): 609.2 (M)+.

EXAMPLE 101 (2R,4S)-4-(1H-Tetrazol-5-yl)-pyrrolidine-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided for Example 28. MS: APCI(AP+): 527.2 (M)+.

EXAMPLE 102 (2R,4S)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided for Example 28,substituting (2R,4S)-4-methoxy-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester for (2R,4R)-4-methoxy-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester. MS: APCI (AP+): 489.2 (M)+.

EXAMPLE 103 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-methyl-imidazol-1-yl)-phenyl]-amide}

The compound was prepared as generally provided for Example 28,substituting 2-Fluoro-4-(2-methyl-imidazol-1-yl)-phenylamine for1-(4-amino-3-fluoro-phenyl)-piperidin-2-one. MS: APCI (AP+): 472.2 (M)+.

EXAMPLE 104 (2R,4R)-4-Cyano-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided for Example 28substituting substituting (2R,4R)-4-cyano-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester for(2R,4R)-4-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester.MS: APCI (AP+): 484.2 (M)+.

EXAMPLE 105 (2R,4R)-4-(1H-Tetrazol-5-yl)-pyrrolidine-1,2-dicarboxylicacid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided for Example 104. MS:APCI (AP−): 525.3 (M)−.

EXAMPLE 106 (2R,4R)-4-Trifluoromethyl-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided for Example 28,(2R,4R)-4-trifluoromethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester for (2R,4R)-4-methoxy-pyrrolidine-1,2-dicarboxylic acid1-tert-butyl ester. MS: APCI (AP+): 527.2 (M)+.

EXAMPLE 107 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-cyano-3-fluoro-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 1,substituting 2-cyanobenzene boronic acid for 2-(methylthio)benzeneboronic acid. MS: APCI (AP+): 493.3 (M)+.

EXAMPLE 108 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-[(2′-aminomethyl-3-fluoro-biphenyl-4-yl)-amide]1-[(4-chloro-phenyl)-amide]

The compound was prepared as generally provided for Example 107. MS:APCI (AP+): 497.3 (M)+.

EXAMPLE 109(2R,4R)-4′-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-3′-fluoro-biphenyl-2-carboxylicacid methyl ester

The compound was prepared as generally provided for Example 107. MS:APCI (AP+): 526.2 (M)+.General Procedure for Example 110

Synthesis of 3: The carboxylic acid (1), aniline or amine (2), EEDQ, andtriethylamine are heated at reflux in chloroform to produce 3.Synthesis of 4: A solution of compound 3, TFA, and DCM is stirred atroom temperature for 1 h and then concentrated under reduced pressure.The resulting oil is dissolved in THF and cooled to 0° C. followed bythe addition of triethylamine or N,N-diisopropylethylamine (DIEA) andthe appropriate isocyanate to produce compound 4.Synthesis of 5: To solution of compound 4 in THF is added potassiumtrimethylsilanolate and is stirred at room temperature overnight toproduce 5.Synthesis of 7: To solution of compound 5 in DMF is addedN,N-diisopropylethylamine, PyBOP, and NHG₁G₂ and is stirred at roomtemperature overnight to produce 7.

EXAMPLE 110 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2,5-dihydro-pyrrole-1-carbonyl)-phenyl]-amide}

Step 1: (2R,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid methyl ester (1)

Cis-4-Hydroxy-D-proline (15 g, 115 mmol) was suspended in 150 mLanhydrous methanol under an argon atmosphere, then cooled to 0° C.before bubbling in HCl gas for 15 minutes. The solution gradually becamehomogenous. The argon and HCl gas lines were removed and the solutionwas refluxed for 4 h. The solution was cooled and then concentratedunder reduced pressure. The crude material was redissolved in 100 mLmethanol and diethyl ether was added until a precipitate formed. Theprecipitate was filtered off, washed with diethyl ether, and dried invacuo overnight to give 1 (20 g, 95%) as a white solid. MS: APCI (AP+):146 (M)+.

Step 2: (2R,4R)-4-Hydroxy-1-trityl-pyrrolidine-2-carboxylic acid methylester (2)

Into a solution of 1 (10 g, 55 mmol) in anhydrous CHCl₃ (100 mL) wasadded triethylamine (19 mL, 138 mmol) and triphenylmethyl chloride (14.5g, 52 mmol). The mixture was stirred at RT for 3 d before concentratingand redissolving in EtOAc. The solution was washed sequentially with 10%aq. citric acid, water, and brine before drying over MgSO₄ andconcentrating under reduced pressure to give 2 (20 g, 100%) as a yellowsolid.

Step 3: (2R,4R)-4-Methoxy-1-trityl-pyrrolidine-2-carboxylic acid methylester (3)

Into a solution of 2 (5.71 g, 14.7 mmol) in anhydrous DMF (20 mL) andanhydrous THF (20 mL) was added MeI (3.67 mL, 58.9 mmol). The solutionwas cooled to 0° C. in an ice bath and NaH (0.766 g, 19.2 mmol) wasadded in one portion. The mixture was stirred at RT for 26 h beforeadding EtOAc and washing sequentially with water and brine. The organiclayer was dried over MgSO₄ and concentrated under reduced pressure.Purification of the crude material by flash chromatography revealed 3(4.67 g, 79%) as a white solid.

Step 4: (2R,4R)-4-Methoxy-pyrrolidine-2-carboxylic acid methyl ester (4)

To a flask containing 3 (4.67 g, 11.6 mmol) was added a solution ofCH₂Cl₂ (27 mL), water (0.3 mL), and TFA (3.0 mL, 38.9 mmol). Thesolution was stirred at RT for 3 h before concentrating under reducedpressure to reveal impure 4. MS: APCI (AP+): 160.1 (M)+.

Step 5: (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester 2-methyl ester (5)

Into a solution of 4 (1.85 g, 11.6 mmol) in CH₂Cl₂ (20 mL) was addedtriethylamine (6.49 mL, 46.5 mmol), di-tert-butyl dicarbonate (5.08 g,23.3 mmol), and dimethylaminopyridine (0.142 g, 1.16 mmol). The mixturewas stirred at RT for 22 h before concentrating under reduced pressureand redissolving in EtOAc. The solution was washed sequentially with 10%aq. citric acid and brine before drying over MgSO₄ and concentratingunder reduced pressure. The crude material was purified by flashchromatography to reveal 5 (2.54 g, 84% over two steps) as a yellowsolid. MS: APCI (AP+): 260.1 (M)+.

Step 6: (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester (6)

Into a solution of 5 (2.54 g, 9.80 mmol) in acetonitrile (20 mL) wasadded water (20 mL) and LiOH.H₂O (1.64 g, 39.2 mmol). The mixture wasstirred at RT for 28 h before removing the acetonitrile under reducedpressure. EtOAc was added to the residue that was then washed with 1NHCl. The aqueous layer was extracted with additional EtOAc and thecombined organic layers were washed with brine and dried over MgSO₄. Thesolution was concentrated under reduced pressure to reveal 6 (2.16 g,90%) as a white solid. MS: APCI (AP−): 244.1 (M)−.

Step 7:(2R,4R)-4-Methoxy-2-(4-methoxycarbonyl-phenylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (7)

Into a solution of 6 (8.11 g, 33.0 mmol) in CHCl₃ (200 mL) was added4-amino-benzoic acid methyl ester (5.00 g, 33.0 mmol), EEDQ (9.81 g,39.6 mmol), and triethylamine (6.9 mL, 49.6 mmol). The solution wasstirred at reflux for 19 h before cooling to RT and adding EtOAc. Thesolution was washed sequentially with 1N HCl, 0.1N NaOH, water, andbrine, before drying over MgSO₄ and concentrating under reduced pressureto give 7 (12.50 g, 100%). MS: APCI (AP+): 379.3 (M)+, (AP−): 377.3(M)−.

Step 8: (2R,4R)-4-[(4-Methoxy-pyrrolidine-2-carbonyl)-amino]-benzoicacid methyl ester (8)

Into a solution of 7 (12.5 g, 33.0 mmol) in anhydrous CH₂Cl₂ (70 mL) wasadded TFA (20 mL). The solution was stirred at RT overnight beforeconcentrating under reduced pressure to give 8 (9.19 g, 100%).

Step 9:(2R,4R)-4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-benzoicacid methyl ester (9)

Into a solution of 8 (9.19 g, 33.0 mmol) in anhydrous THF (200 mL) at 0°C. was added N,N-diisopropylethylamine (DIEA) (28.7 mL, 165 mmol) and4-chlorophenyl isocyanate (5.07 g, 33.0 mmol). The solution was stirredat RT overnight before concentrating under reduced pressure. The crudematerial was purified on a silica gel column eluted with 10% moving to50% EtOAc in hexanes. Combined and concentrated pure fractions.Remaining EtOAc was azeotroped off with acetonitrile and was lyophilizedfrom acetonitrile/water to give 9 (13.37 g, 94%) as a solid. MS: APCI(AP+): 432.1 (M)+, (AP−): 430.1 (M)−.

Step 10:(2R,4R)-4-{[1-(4-Chloro-phenylcarbamoyl)-4-methoxy-pyrrolidine-2-carbonyl]-amino}-benzoicacid (10)

Into a solution of 9 (3.0 g, 6.94 mmol) in THF (50 mL) was addedpotassium trimethylsilanolate (3.85 g, 27.3 mmol). The solution wasstirred at RT for 48 h before concentrating under reduced pressure andadding EtOAc. The solution was washed sequentially with 1N HCl, andbrine, before drying over MgSO₄ and concentrating under reduced pressureto give 10 (2.9 g, 100%). MS: APCI (AP+): 418.1 (M)+, (AP−): 416.1 (M)−.

Step 11: (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2,5-dihydro-pyrrole-1-carbonyl)-phenyl]-amide}(11)

Into a solution of 10 (0.25 g, 0.589 mmol) in DMF (3 mL) was addedN,N-diisopropylethylamine (DIEA) (0.4 mL, 2.32 mmol), PyBOP (0.34 g,0.653 mmol), and 3-pyrroline (0.09 mL, 1.19 mmol). The solution wasstirred at RT for 19 h and EtOAc added. The solution was washedsequentially with 1N HCl, saturated NaHCO₃, water, and brine, beforedrying over MgSO₄ and concentrating under reduced pressure. The crudematerial was purified on a silica gel column eluted with 20% EtOAc inhexanes moving to 1% MeOH in EtOAc. Combined and concentrated purefractions. Remaining EtOAc was azeotroped off with acetonitrile and waslyophilized from acetonitrile/water to give 11 (0.116 g, 41%) as asolid. MS: APCI (AP+): 469.2 (M)+, (AP−): 468.1 (M)−.

General Procedure for Example 111

Synthesis of 2: The carboxylic acid (1) is converted to the acidchloride (2) upon treatment with oxalyl chloride and DMF (catalytic) indichloromethane.Synthesis of 3: To the acid chloride (2) in dichloromethane is thenadded NHG₁G₂ and triethylamine in dichloromethane. Alternatively NHG₁G₂can be coupled directly to the carboxylic acid with addition of PyBOPand N,N-diisopropylethylamine in DMF. Reduction of the nitro group tothe corresponding aniline is readily achieved with a transition metalsuch as palladium on carbon or Raney nickel and hydrogen to give 3.Synthesis of 5: The carboxylic acid (4), aniline (3), EEDQ, andtriethylamine are heated at reflux in chloroform to produce 5.Synthesis of 6: A solution of compound 5, TFA, and DCM is stirred atroom temperature for 1 h and then concentrated under reduced pressure.The resulting oil is dissolved in THF and cooled to 0° C. followed bythe addition of triethylamine or N,N-diisopropylethylamine (DIEA) andthe appropriate isocyanate to produce compound 6.

EXAMPLE 111 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-dimethylcarbamoyl-2-fluoro-phenyl)-amide]

Step 1: (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butylester (1)

Cis-4-hydroxy-D-proline (15 g, 114 mmol) was dissolved In 150 mL ofTHF/H₂O (2:1), added 2M aqueous NaOH solution (86 mL, 172 mmol),followed by Boc₂O (27 g, 126 mmol). Reaction was stirred at ambienttemperature overnight. The solution was acidified with 10% citric acidthen extracted with EtOAc (2×250 mL), washed with water, brine, driedorganics with MgSO₄, filtered and concentrated to give 1 (16 g, 61%)APCI (AP−): 230.1 (M−H)⁻.

Step 2:(2R,4R)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylicacid 1-tert-butyl ester (2)

(2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester(16 g, 69 mmol) was dissolved in 100 mL DMF, added imidazole (12 g, 173mmol), dimethylaminopyridine (0.85 g, 6.9 mmol), andtert-butyldimethylsilyl chloride (12.5 g, 83 mmol). Stirred at ambienttemperature overnight, dissolved in 350 mL EtOAc, washed with 10% citricacid (3×200 mL), water (2×200 mL), brine, dried with MgSO₄, filtered,and concentrated to give 2 (20 g, 84%) APCI (AP−): 344.2 (M−H)⁻.

Step 3: 3-Fluoro-4-nitro-benzoyl chloride (3)

Into a solution of 3-fluoro-4-nitro-benzoic acid (4.0 g, 21.6 mmol) inanhydrous CH₂Cl₂ (200 mL) at 0° C. was slowly added oxalyl chloride(2.45 mL, 28.0 mmol) and a drop of DMF. The solution was stirred andallowed to warm to RT overnight before concentrating under reducedpressure to give 3 (4.39 g, 100%).

Step 4: 3-Fluoro-N,N-dimethyl-4-nitro-benzamide (4)

Into a solution of 3 (1.50 g, 7.36 mmol) in CH₂Cl₂ (30 mL) at 0° C. wasadded triethylamine (1.5 mL, 10.9 mmol) and dimethylamine 40% in water(0.83 mL, 7.36 mmol) dropwise. The solution was stirred and allowed towarm to RT overnight before concentrating under reduced pressure andadding EtOAc. The solution was washed sequentially with saturatedNaHCO₃, water, and brine, before drying over MgSO₄ and concentratingunder reduced pressure to give impure 4 (0.78 g, 50%). MS: APCI (AP+):213.1 (M)+, (AP−): 212.1 (M)−.

Step 5: 4-Amino-3-fluoro-N,N-dimethyl-benzamide (5)

To a Parr apparatus was added 4 (0.78 g, 3.67 mmol), Raney nickel (1.2g), and THF (50 mL). The vessel was sealed under a hydrogen atmosphereand shaken under pressure at room temperature for 15 h. The vessel wasthen depressurized and the solids filtered off, washing with THF. Thefiltrate was concentrated under reduced pressure to give impure 5 (0.66g, 100%). MS: APCI (AP+): 183.1 (M)+, (AP−): 181.0 (M)−.

Step 6:(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-(4-dimethylcarbamoyl-2-fluoro-phenylcarbamoyl)-pyrrolidine-1-carboxylicacid tert-butyl ester (6)

Into a solution of 2 (1.25 g, 3.61 mmol) in CHCl₃ (25 mL) was added 5(0.66 g, 3.61 mmol), EEDQ (1.07 g, 4.32 mmol), and triethylamine (0.74mL, 5.33 mmol). The solution was stirred at reflux for 19 h beforecooling to RT and adding EtOAc. The solution was washed sequentiallywith 1N HCl, 0.1N NaOH, water, and brine, before drying over MgSO₄ andconcentrating under reduced pressure. The crude material was purified ona silica gel column eluted with 20% moving to 50% EtOAc in hexanes.Combined and concentrated pure fractions to give 6 (0.33 g, 18%). MS:APCI (AP+): 510.3 (M)+, (AP−): 508.4 (M)−.

Step 7: (2R,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid(4-dimethylcarbamoyl-2-fluoro-phenyl)-amide (7)

Into a solution of 6 (0.33 g, 0.647 mmol) in anhydrous CH₂Cl₂ (10 mL)was added TFA (2 mL). The solution was stirred at RT for 4 h beforeconcentrating under reduced pressure to give 7 (0.19 g, 100%).

Step 8: (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-dimethylcarbamoyl-2-fluoro-phenyl)-amide](8)

Into a solution of 7 (0.19 g, 0.643 mmol) in anhydrous THF (10 mL) at 0°C. was added N,N-diisopropylethylamine (DIEA) (0.56 mL, 3.21 mmol) and4-chlorophenyl isocyanate (0.099 g, 0.643 mmol). The solution wasstirred at RT overnight before concentrating under reduced pressure.Crystallized from EtOAc in hexanes and filtered to give 8 (0.12 g, 43%)as a solid. MS: APCI (AP+): 449.2 (M)+, (AP−): 447.1 (M)−.

EXAMPLE 112 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(pyrrolidine-1-carbonyl)-phenyl]-amide}

The compound was prepared as generally provided for Example 111. MS:APCI (AP+): 457.1 (M)+, (AP−): 455.1 (M)−.

EXAMPLE 113 Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(pyrrolidine-1-carbonyl)-phenyl]-amide}

The compound was prepared as generally provided for Example 111. MS:APCI (AP+): 441.1 (M)+, (AP−): 439.1 (M)−.

EXAMPLE 114 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2-methyl-pyrrolidine-1-carbonyl)-phenyl]-amide}

The compound was prepared as generally provided for Example 111. MS:APCI (AP+): 471.2 (M)+, (AP−): 469.2 (M)−.

EXAMPLE 115 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(ethyl-methyl-carbamoyl)-phenyl]-amide}

The compound was prepared as generally provided for Example 111. MS:APCI (AP+): 445.2 (M)+, (AP−): 443.1 (M)−.

EXAMPLE 116 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-dimethylcarbamoyl-phenyl)-amide]

The compound was prepared as generally provided for Example 111. MS:APCI (AP+): 431.1 (M)+, (AP−): 429.1 (M)−.

EXAMPLE 117 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2R-methyl-pyrrolidine-1-carbonyl)-phenyl]-amide}

The compound was prepared as generally provided for Example 111. MS:APCI (AP+): 471.2 (M)+, (AP−): 469.2 (M)−.

EXAMPLE 118 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(2S-methyl-pyrrolidine-1-carbonyl)-phenyl]-amide}

The compound was prepared as generally provided for Example 111. MS:APCI (AP+): 471.2 (M)+, (AP−): 469.2 (M)−.

EXAMPLE 119 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(pyrrolidine-1-carbonyl)-phenyl]-amide}

The compound was prepared as generally provided for Example 111. MS:APCI (AP+): 475.2 (M)+, (AP−): 473.1 (M)−.

EXAMPLE 120 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(pyrrolidine-1-carbonyl)-2-pyrrolidin-1-yl-phenyl]-amide}

The compound was prepared as generally provided for Example 111. MS:APCI (AP+): 526.2 (M)+, (AP−): 524.3 (M)−.

EXAMPLE 121(2R,4R)-4-{[1-(4-Chloro-phenylcarbamoyl)-4-hydroxy-pyrrolidine-2-carbonyl]-amino}-3-pyrrolidin-1-yl-benzoicacid methyl ester

The compound was prepared as generally provided for Example 111. MS:APCI (AP+): 487.2 (M)+, (AP−): 485.2 (M)−.

EXAMPLE 122 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(azetidine-1-carbonyl)-phenyl]-amide}1-[(4-chloro-phenyl)-amide]

The compound was prepared as generally provided for Example 111o. MS:APCI (AP+): 443.2 (M)+, (AP−): 441.1 (M)−.

EXAMPLE 123 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[2-fluoro-4-(pyrrolidine-1-carbonyl)-phenyl]-amide}

The compound was prepared as generally provided for Example 111.Formation of the 5-chloro-pyridin-2-yl moiety can be found in Example26. MS: APCI (AP+): 476.2 (M)+, (AP−): 474.2 (M)−.

EXAMPLE 124 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-{[4-(pyrrolidine-1-carbonyl)-phenyl]-amide}

The compound was prepared as generally provided for Example 111.Formation of the 5-chloro-pyridin-2-yl moiety can be found in Example26. MS: APCI (AP+): 458.2 (M)+, (AP−): 456.2 (M)−.

EXAMPLE 125 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(5-chloro-pyridin-2-yl)-amide]2-[(4-dimethylcarbamoyl-phenyl)-amide]

The compound was prepared as generally provided for Example 111.Formation of the 5-chloro-pyridin-2-yl moiety can be found in Example26. MS: APCI (AP+): 432.1 (M)+, (AP−): 430.1 (M)−.

EXAMPLE 126(2R,4R)-4-{[1-(4-Chloro-phenylcarbamoyl)-4-hydroxy-pyrrolidine-2-carbonyl]-amino}-3-dimethylamino-benzoicacid methyl ester

The compound was prepared as generally provided for Example 111. MS:APCI (AP+): 461.2 (M)+, (AP−): 459.1 (M)−.

EXAMPLE 127 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(pyrrolidine-1-carbonyl)-phenyl]-amide}

The compound was prepared as generally provided for Example 110 and/orDD-2. MS: APCI (AP+): 471.2 (M)+, (AP−): 469.2 (M)−.

EXAMPLE 128 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-dimethylcarbamoyl-phenyl)-amide]

The compound was prepared as generally provided for Example 110 and/or111. MS: APCI (AP+): 445.2 (M)+, (AP−): 443.2 (M)−.

EXAMPLE 129 (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[4-(pyrrolidine-1-carbonyl)-phenyl]-amide}

The compound was prepared as generally provided for Example 111. MS:APCI (AP+): 485.3 (M)+, (AP−): 483.3 (M)−.

EXAMPLE 130 (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-dimethylcarbamoyl-phenyl)-amide]

The compound was prepared as generally provided for Example 111. MS:APCI (AP+): 459.2 (M)+, (AP−): 457.2 (M)−.

EXAMPLE 131 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(pyrrolidine-1-carbonyl)-phenyl]-amide}

The compound was prepared as generally provided for Example 110 and/or111. MS: APCI (AP+): 489.3 (M)+, (AP−): 487.2 (M)−.

EXAMPLE 132 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-dimethylcarbamoyl-2-fluoro-phenyl)-amide]

The compound was prepared as generally provided for Example 110 and/or111. MS: APCI (AP+): 463.2 (M)+, (AP−): 461.2 (M)−.

EXAMPLE 133 (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(pyrrolidine-1-carbonyl)-phenyl]-amide}

The compound was prepared as generally provided for Example 111 MS: APCI(AP+): 503.3 (M)+, (AP−): 501.3 (M)−.

EXAMPLE 134 (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(4-dimethylcarbamoyl-2-fluoro-phenyl)-amide]

The compound was prepared as generally provided for Example 111. MS:APCI (AP+): 477.3 (M)+, (AP−): 475.2 (M)−.

EXAMPLE 135 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-methyl-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided for Example 28. MS: APCI(AP+): 485.3 (M)+, (AP−): 483.3 (M)−.

EXAMPLE 136 (2R,4R)-4-Ethoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-methyl-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided for Example 28. MS: APCI(AP+): 499.2 (M)+, (AP−): 497.2 (M)−.

EXAMPLE 137 Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-fluoro-4-quinolin-8-yl-phenyl)-amide]

The compound was prepared as generally provided for Example 19. MS: APCI(AP+): 489.1 (M)+, (AP−): 488.1 (M)−.

EXAMPLE 138 Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3,5-difluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 19. MS: APCI(AP+): 534.1 (M)+, (AP−): 532.0 (M)−.

EXAMPLE 139 Pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfonyl-2-methyl-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 19. MS: APCI(AP+): 512.1 (M)+, (AP−): 510.1 (M)−.

EXAMPLE 140 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfonyl-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 17. MS: APCI(AP+): 514.0 (M)+, (AP−): 512.0 (M)−.

EXAMPLE 142 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfinyl-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 17. MS: APCI(AP+): 498.2 (M)+, (AP−): 496.2 (M)−.

EXAMPLE 143 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(3-methyl-2′-methylsulfanyl-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 17. MS: APCI(AP+): 496.1 (M)+, (AP−): 494.1 (M)−.

EXAMPLE 144 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 17. MS: APCI(AP+): 532.0 (M)+, (AP−): 530.0 (M)−.

EXAMPLE 145 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfonyl-3-methyl-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 17. MS: APCI(AP+): 528.1 (M)+, (AP−): 526.1 (M)−.

EXAMPLE 146 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methanesulfonyl-3-trifluoromethyl-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 17. MS: APCI(AP+): 582.1 (M)+, (AP−): 580.1 (M)−.

EXAMPLE 147 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-methoxy-biphenyl-4-yl)-amide]

Step 1: 2-Methoxy-4′-nitro-biphenyl (147a)

1-Bromo-4-nitrobenzene (1.00 g, 4.95 mmol), 2-methoxyphenylboronic acid(1.13 g, 7.43 mmol), K₃PO₄ (1.58 g, 7.43 mmol), and anhydrous DMF (5 mL)were combined in a flask and degassed with argon.Tetrakistriphenylphosphine palladium(0) (0.858 g, 0.743 mmol) was addedto the mixture which was again degassed with argon. The mixture washeated at 110° C. for 3 h before cooling, diluting with EtOAc, andfiltering through a plug of silica gel. The solution was washedsequentially with water and brine before drying over MgSO₄. The solutionwas concentrated under reduced pressure and purified by flashchromatography to provide 147-a (1.05 g, 93%) as a yellow solid. MS:APCI (AP+): 230.1 (M)+.

Step 2: 2′-Methoxy-biphenyl-4-ylamine (147-b)

To a Parr apparatus was added 147-a (1.05 g, 4.58 mmol), Raney nickel(0.66 g), and a 4:1 mixture of THF:MeOH (50 mL). The vessel was sealedunder a hydrogen atmosphere and shaken under pressure at RT for 18 h.The vessel was then depressurized and the solids filtered off, washingwith THF. The filtrate was concentrated under reduced pressure to revealan unknown amount of 147-b as a tan oil that was carried on withoutfurther purification. MS: APCI (AP+): 200.0 (M)+.

The title compound (147) was prepared from 147b as generally providedfor in Examples 26 28. MS: APCI (AP+): 466.1 (M)+.

EXAMPLE 148 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-hydroxy-biphenyl-4-yl)-amide]

In a flask was dissolved 147a (0.100 g, 0.215 mmol) in anhydrous DCM (5mL). At 0° C., boron tribromide (0.203 mL, 2.15 mmol) was addeddropwise. The solution was stirred at RT for 25 min before concentratingunder reduced pressure. The crude material was purified by silica gelflash chromatography followed by lyophilization from acetonitrile/waterto provide the title compound (0.039 g, 40%) as a white solid. MS: APCI(AP+): 452.1 (M)+.

EXAMPLE 149 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2-fluoro-4-iodo-phenyl)-amide]

The compound was prepared as generally provided for Example 28. MS: APCI(AP+): 518.0 (M)+.

EXAMPLE 150 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide}

The compound was prepared as generally provided for Example 28. MS: APCI(AP+): 485.2 (M)+.

EXAMPLE 151 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-hydroxy-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 28 andExample 3, step 3a. MS: APCI (AP+): 486.2 (M)+.

EXAMPLE 152 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-hydroxy-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 28. MS: APCI(AP+): 505.3 (M)+.

EXAMPLE 153 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-hydroxy-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 28. MS: APCI(AP+): 490.3 (M)+.

EXAMPLE 154 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-hydroxy-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 28. MS: APCI(AP+): 476.2 (M)+.

EXAMPLE 155 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-hydroxy-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 28. MS: APCI(AP+): 477.2 (M)+.

EXAMPLE 156 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-hydroxy-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 28. MS: APCI(AP+): 561.3 (M)+.

EXAMPLE 157 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-hydroxy-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 28. MS: APCI(AP+): 515.2 (M)+.

EXAMPLE 158 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-hydroxy-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 28 andExample 23, step 3a. MS: APCI (AP+): 516.2 (M)+.

EXAMPLE 159 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-hydroxy-biphenyl-4-yl)-amide]

Step 1: 3-Methyl-1-(4-nitro-phenyl)-1H-pyridin-2-one (159-a)

1-Iodo-4-nitrobenzene (1.61 g, 6.45 mmol) was combined with3-methyl-2-pyridone (0.845 g, 7.74 mmol), CuI (0.246 g, 1.29 mmol), andK₃PO₄ (2.74 g, 12.9 mmol). 1,4-Dioxane (6 mL) was added followed bytrans-1,2-diaminocyclohexane (0.194mL, 1.61 mmol). The mixture washeated to reflux for 19 h before cooling and diluting with EtOAc. Themixture was filtered through a plug of silica, eluting with EtOAc, andthe filtrate concentrated under reduced pressure. Purification of thecrude product by flash chromatography provided 159-a (0.528 g, 36%) as abrown solid. MS: APCI (AP+): 231.1 (M)+.

Step 2: 1-(4-Amino-phenyl)-3-methyl-1H-pyridin-2-one (159-b)

To a flask was added 159a (0.523 g, 2.27 mmol), glacial acetic acid (7.6mL), conc. HCl (3.8 mL, 45.4 mmol), and mossy tin (0.539 g, 4.54 mmol).The mixture was heated to reflux for 90 min before cooling andconcentrating under reduced pressure. The residue was dissolved in EtOAcand washed with aq. 1N NaOH until shown basic with pH paper. The aqueouslayer was extracted twice with EtOAc and the combined organics washedwith brine and dried over MgSO₄. After placing under vacuum, 159-b(0.407 g, 89%) was revealed as a tan solid that was carried on withoutfurther purification. MS: APCI (AP+): 201.1 (M)+.

The title compound (159) was prepared from 159-b as generally providedfor Example 28. MS: APCI (AP+): 481.3 (M)+.

EXAMPLE 160 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-hydroxy-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 159 andExample 3, step 3a. MS: APCI (AP+): 482.3 (M)+.

EXAMPLE 161 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-hydroxy-biphenyl-4-yl)-amide]

Step 1: 4-(4-Nitro-phenyl)-morpholine (161-a)

1-Fluoro-4-nitrobenzene (3.00 mL, 28.3 mmol) was combined in a flaskwith anhydrous 2-propanol (28 mL), triethylamine (4.34 mL, 31.1 mmol),and morpholine (2.47 mL, 28.3 mmol). The mixture was refluxed for 3.5 hbefore adding additional morpholine (2.47 mL, 28.3 mmol) and refluxingfor 20 h. The mixture was then cooled and concentrated under reducedpressure. Purification by silica gel flash chromatography provided 161-a(6.09 g, 98%) as a 95% pure solid. MS: APCI (AP−): 207.1 (M)−.

The title compound (161) was prepared from 161-a as generally providedfor 147 and Example 28. MS: APCI (AP+): 459.3 (M)+.

EXAMPLE 162 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-hydroxy-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for in Example 28 and147. MS: APCI (AP+): 471.3 (M)+.

EXAMPLE 163 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-hydroxy-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for in Example 3, step3a, and Example 162. MS: APCI (AP+): 472.2 (M)+.

EXAMPLE 164 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-hydroxy-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 28. MS: APCI(AP+): 499.2 (M)+.

EXAMPLE 165 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-hydroxy-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for Example 28 andExample 3, step 3a. MS: APCI (AP+): 500.2 (M)+.General Procedure for Examples 166-173:

Synthesis of 2: A mixture of 1 (where Z is a halide), B (where B is anitrogen in a ring), K₂CO₃, CuI, and 8-hydroxyquinoline is heated inDMSO at 130° C. to obtain compound 2.Synthesis of 4: The appropriate aniline (2), EEDQ, triethylamine andcarboxylic acid (3) are heated at reflux in chloroform to produce 4.Synthesis of 5: A solution of compound 4, TFA and DCM is stirred at roomtemperature for 1 h and then concentrated under reduced pressure. Theresulting oil is dissolved in THF and cooled to 0° C. followed by theaddition of triethylamine and the appropriate isocyanate to producecompound 5.

EXAMPLE 167 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-hydroxy-biphenyl-4-yl)-amide]

Step 1: 1-(4-Amino-3-fluoro-phenyl)-5-methyl-1H-pyridin-2-one (167-a)

2-Fluoro-4-iodoaniline (0.905 g, 42.2 mmol) was combined with5-methyl-1H-pyridin-2-one (0.500 g, 4.58 mmol), 8-hydroxyquinoline(0.083 g, 0.573 mmol), CuI (0.109 g, 0.0.573 mmol), and K₂CO₃ (0.580 g,4.20 mmol), in DMSO (3 mL). The mixture was degassed with a stream ofargon and then heated at reflux for 16 h before cooling to RT. 10% aq.NH₄OH and EtOAc were added, and the mixture was filtered through a plugof layered celite and decolorizing charcoal, eluting with EtOAc. Thefiltrate was concentrated under reduced pressure. Purification of thecrude product by silica gel flash chromatography revealed 167-a (0.673g, 81%) as awhite solid. MS: APCI (AP+): 219.1 (M)+.

The title compound (167) was prepared from 167-a as generally providedfor in Example 28. MS: APCI (AP+): 499.2 (M)+.

EXAMPLE 168 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-hydroxy-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for in Example andExample 3, step 3a. MS: APCI (AP+): 500.2 (M)+.

EXAMPLE 169 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-hydroxy-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for in Example 167. MS:APCI (AP+): 515.2 (M)+.

EXAMPLE 170 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-hydroxy-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for in Example 168. MS:APCI (AP+): 516.2 (M)+.

EXAMPLE 171 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-hydroxy-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for in Example 167. MS:APCI (AP+): 499.2 (M)+.

EXAMPLE 172 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-hydroxy-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for in Example 168. MS:APCI (AP+): 500.2 (M)+.

EXAMPLE 173 (2R,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid1-[(4-chloro-phenyl)-amide]2-[(2′-hydroxy-biphenyl-4-yl)-amide]

The compound was prepared as generally provided for in Example 167. MS:APCI (AP+): 499.2 (M)+.

EXAMPLE 174 (2R,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid2-{[4-(5-chloro-2-oxo-2H-pyridin-1-yl)-2-fluoro-phenyl]-amide}1-[(4-chloro-phenyl)-amide]

The compound was prepared as generally provided for in Example 167. MS:APCI (AP+): 519.1 (M)+.

General Procedure for the Preparation of Examples 175-181

Route 1

Synthesis of 2:

Aniline 1 is converted to an acrylamide 2 by the addition of acryoylchloride and a base, such as saturated sodium bicarbonate, in a solventsuch as ethyl acetate at room temperature. Alternatively, the anilinemay be converted to 2 by the addition of an acrylic acid and adding acoupling reagent such as dicyclohexylcarbodi-imide (DCC),O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), or EEDQ.

Synthesis of 3 and 4:

To the acrylamide 2 is added an excess of trimethylsilyl diazomethane ina solvent such as ethyl acetate or dichloromethane. The resultingdihydropyrazole 3 may then be treated with an isocyanate, in thepresence of base such as pyridine or triethylamine, in a solvent such asdichloromethane, to afford compound 4.

Synthesis of 5-8:

The chemistry for the preparation of compounds 5-8 is similar to thatdescribed in Route 1.

Synthesis of 9:

Compound 8 may be converted to 9 by a Suzuki coupling with a boronicacid, although other coupling conditions commonly known to the skilledpractitioner may also be used. This route is particularly useful forcompounds containing a biaryl A-B group. In situations where atert-butylsulphonamide is present in B, which occurs in some of theparticularly preferred compouinds, the sulphonamide may be formed bystirring with trifluoroacetic acid for 16 h.

Synthesis of 10:

The synthetic routes commences with formation of acrylamide 10 asdescribed for Route 1.

Synthesis of 11:

Ethyl diazoacetate is mixed with acrylamide 10 to afford theappropriately substituted dihydropyrazole 11.

Synthesis of 12 and 13:

Similar chemistry to that described in Route 1 allows conversion of 11to 12. Reduction of the ester moietry in 12 is then achieved using areducing agent such as super-hydride to afford the alcohol 13.

Route 4

Alternatively compounds may be prepared according to scheme 2d. Here theacrylic ester (14) is reacted with a diazocompound to form thedihydropyrazole (15). Addition of a chloroformate affords compounds offormula (16). Deprotection of the ester is achieved by acid, such as TFAor hydrogen chloride to afford compounds of formula (17). Addition of ananiline with a coupling reagent such as EEDQ and base affords compoundsof formula (18). Deprotection of the carbamate with Pd/C and hydrogenaffords compounds of formula (19) which may then be reacted withisocyanates to afford compounds of formula (20)

EXAMPLE 175 5-Methyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]

Step 1:N-(2′-tert-Butylsulfamoyl-3-fluoro-biphenyl-4-yl)-2-methyl-acrylamide

To 4′-Amino-3′-fluoro-biphenyl-2-sulfonic acid tert-butylamide (5.000 g,15.51 mmoles) at room temperature in ethyl acetate (50 ml) was addedsaturated sodium bicarbonate, aqueous, 50 ml and then 2-methyl-acryloylchloride (1.25 equiv.). Stirred for 2 hours then added a further 1 ml ofthe acid chloride. After 2 hours an aliquot showed product by NMR.Product seems to co-run with starting material. Extracted into ethylacetate, washed with brine, dried MgSO₄, and then concentrated in vacuo.Collected some crystalline product from ethyl acetate hexane, 0.48 g.Columned mother liquor to afford product. Combined with previouslycrystallized fraction to affordN-(2′-tert-Butylsulfamoyl-3-fluoro-biphenyl-4-yl)-2-methyl-acrylamide(4.520 g). APCI (AP+): 391 (M+H)+.

Step 2: 3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide

To N-(2′-tert-Butylsulfamoyl-3-fluoro-biphenyl-4-yl)-2-methyl-acrylamide(0.525 g) in ethyl acetate (3.5 ml) was added 2M trimethylsilyldiazomethane (3.5 ml) and the mixture stirred at room temperatureovernight. NMR indicated complete reaction. Evaporated and thendissolved in acetonitrile (20 ml) and treated with aq. HF (1 ml).Stirred for 1 h. Added sat. NaHCO₃ (5 ml), extracted into EtOAc (25 ml).Washed with brine, dried MgSO₄, evaporated in vacuo from methylenechloride to afford a white foam of the product:3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide (0.592 g).APCI(AP+): 433 (M+H)+.

Step 3: 5-Methyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid5-[(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide]1-[(4-chloro-phenyl)-amide]

To a solution of 3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide (0.416 g) inmethylene chloride (4 ml) was added pyridine (1 ml) and 4-chlorophenylisocyanate (1.25 g). Stirred at room temperature for 16 hours. A furtheramount of 4-chlorophenyl isocyanate (0.200 g) and pyridine (0.2 ml) wasadded. Stirred for 48 hours. Columned, silica gel—eluant 10-100 EtOAc inhexane over 25 mins. Affords:5-methyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid5-[(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide]1-[(4-chloro-phenyl)-amide];0.365 g

Step 4: 5-Methyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]

To 5-methyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid5-[(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-yl)-amide]1-[(4-chloro-phenyl)-amide](0.300g) was added trifluoroacetic acid (10.0 g). Stirred at room temperatureovernight and then evaporated the TFA. Redissolved in hot methanol andadded water until cloudy white. Lyophilized to afford5-methyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]0.256 g. APCI (AP+): 530 (M+H)⁺

EXAMPLE 176 3-Hydroxymethyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

Step 1: N-(3-Fluoro-2′-methanesulfonyl-biphenyl-4-yl)-acrylamide

To 3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylamine (8.510 g) in ethylacetate (400 ml) was added sat. NaHCO3 (100 ml) and then acryolylchloride (1.3 equiv.). Stirred at room temperature for 3 hours. WashedEtOAc extract with brine, dried over MgSO₄ and evaporated in vacuo.Triturated with ether and then filtered to affordN-(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-acrylamide (9.670 g, 94%).

Step 2:5-(3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-4,5-dihydro-1H-pyrazole-3-carboxylicacid ethyl ester

To N-(3-Fluoro-2′-methanesulfonyl-biphenyl-4-yl)-acrylamide (4.47 g) inethyl acetate (150 ml) was added ethyl diazoacetate (1.5 equiv.) and themixture heated at 60° C. for 24 hours. Evaporated and then columned:eluant 10-100 EtOAc in hexane. Collected5-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-4,5-dihydro-1H-pyrazole-3-carboxylicacid ethyl ester (1.67 g)

Step 3:1-(4-Chloro-phenylcarbamoyl)-5-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-4,5-dihydro-1H-pyrazole-3-carboxylicacid ethyl ester

To a solution of5-(3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-4,5-dihydro-1H-pyrazole-3-carboxylicacid ethyl ester (1.520 g) in methylene chloride (12 ml) was addedpyridine (4 equiv.) and 4-chlorophenyl isocyanate (1.25 equiv.). Stirredat room temperature for 16 hours. Evaporated and recorded crude 1H:80156×134RM1—revealed expected product and relatively clean. Purified bysilica gel chromatography, eluant 10-100% EtOAc in hexane over 25 mins.Collected1-(4-chloro-phenylcarbamoyl)-5-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-4,5-dihydro-1H-pyrazole-3-carboxylicacid ethyl ester (1.480 g).

Step 4: 3-Hydroxymethyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

To a solution of1-(4-Chloro-phenylcarbamoyl)-5-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-4,5-dihydro-1H-pyrazole-3-carboxylicacid ethyl ester (0.228 g) in THF (3 ml) at 0° C. was added a 1Msolution of super-hydride in THF (1.17 ml). Stirred for 30 mins and thenquenched with sat. NH₄Cl. Extracted into EtOAc and washed with brine.Evaporated in vacuo. Crude 1H indicated clean reaction to product.Column—eluant 0-5% methanol in ethyl acetate. Affords3-Hydroxymethyl-4,5-dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]afterlyophilization from MeCN/H2O: 0.230 g; MS (APCI) +ve: 545

EXAMPLE 177 4,5-Dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]

This compound was prepared using the same procedures as found forExample 175 with acryloyl chloride substituted for 2-Methyl-acryloylchloride in step 1. APCI (AP−): 514 (M−H)⁻.

EXAMPLE 178 (5R) 4,5-Dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-[(3-fluoro-2′-sulfamoyl-biphenyl-4-yl)-amide]

This compound was prepared using the same procedures as found forExample 177 and the enantiomers separated by chiral HPLC Column: ChrialPak AD 250×4.6 mm; 254 nm, mobile phase: Hexane (20); Ethanol (20);Methanol (60) Affords: (R) enantiomer @ 11.038 mins APCI (AP−): 514(M−H)⁻ and (S) enantiomer @ 36.084 mins APCI (AP−): 514 (M−H)⁻.

EXAMPLE 179 4,5-Dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-{[2-fluoro-4-(2-oxo-piperidin-1-yl)-phenyl]-amide}

This compound was prepared using the same procedures as found forExample 175 with acryloyl chloride substituted for 2-Methyl-acryloylchloride in step 1 and 1-(4-Amino-3-fluoro-phenyl)-piperidin-2-onesubsubstituted for 4′-Amino-3′-fluoro-biphenyl-2-sulfonic acidtert-butylamide. APCI (AP−): 456 (M−H)⁻.

EXAMPLE 180 4,5-Dihydro-pyrazole-1,5-dicarboxylic acid1-[(4-chloro-phenyl)-amide]5-[(3-fluoro-2′-methanesulfonyl-biphenyl-4-yl)-amide]

This compound was prepared using the same procedures as found forExample 177 with acryloyl chloride substituted for 2-Methyl-acryloylchloride in step 1 and 3-Fluoro-2′-methanesulfonyl-biphenyl-4-ylaminesubstituted for 4′-Amino-3′-fluoro-biphenyl-2-sulfonic acidtert-butylamide. APCI (AP−): 513 (M−H)⁻

EXAMPLE 1811-(4-Chloro-phenylcarbamoyl)-5-(3-fluoro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-4,5-dihydro-1H-pyrazole-3-carboxylicacid ethyl ester

This compound was prepared using the same procedures as found forExample 176 wherein step 4 was omitted. APCI (AP−): 585 (M−H)⁻.

EXAMPLE 182 Formulations

The compounds of the present invention can be administered alone or incombination with one or more therapeutic agents. These include, forexample, other anticoagulant, antiplatelet, or platelet inhibitoryagents which include non-steroidal anti-inflammatory agents such asaspirin, ibuprofen, naproxen sodium, indomethacin, piroxica, andticlopidine; thrombin inhibitors such as argatroban, efegatran,inogatran, factor VIa inhibitors, thrombolytic or fibrinolytic agentssuch as tissue plasminogen activator, urokinase or streptokinase; GPIIb-IIIa antagonists, and P2Y12 antagonists.

The compounds are thus well suited to formulation for convenientadministration to mammals for the prevention and treatment of suchdisorders.

The following examples further illustrate typical formulations providedby the invention. Formulation 1 Ingredient Amount compound of FormulasI-V 0.5 to 800 mg sodium benzoate 5 mg isotonic saline 1000 mL

The above ingredients are mixed and dissolved in the saline for IVadministration to a human suffering from, for example, arterialthrombosis. Formulation 2 Ingredient Amount compound of Formulas I-V 0.5to 800 mg cellulose, microcrystalline 400 mg stearic acid 5 mg silicondioxide 10 mg sugar, confectionery 50 mg

The ingredients are blended to uniformity and pressed into a tablet thatis well suited for oral administration to a human for preventing, forexample, cerebral infarction. Formulation 3 Ingredient Amount compoundof Formulas I-I 0.5 to 800 mg starch, dried 250 mg magnesium stearate 10mg

The ingredients are combined and milled to afford material suitable forfilling hard gelatin capsules administered to humans suffering from, forexample, venous thrombosis. Formulation 4 Ingredient Amount % wt./(totalwt.) compound of Formulas I-I  1 to 50 Polyethylene glycol 1000 32 to 75Polyethylene glycol 4000 16 to 25

The ingredients are combined via melting and then poured into moldscontaining 2.5 g total weight.

While embodiments of the invention have been illustrated and described,it is not intended that these embodiments illustrate and describe allpossible forms of the invention. Rather, the words used in thespecification are words of description rather than limitation, and it isunderstood that various changes may be made without departing from thespirit and scope of the invention.

1. A compound selected from: 1-(4-Amino-3-fluorophenyl)piperidin-2-one,2-Fluoro-4-(3-methylpyrazol-1-yl)phenylamine,2-Fluoro-4-(5-methylpyrazol-1-yl)phenylamine,1-(4-Amino-3-fluorophenyl)-1H-pyridin-2-one,6′-Amino-3,4,5,6-tetrahydro-[1,3′]bipyridinyl-2-one,6′-Amino-[1,3′]bipyridinyl-2-one,2-(4-Amino-3-fluorophenyl)-2H-pyridazin-3-one,1-(4-Aminophenyl)-3-methyl-1H-pyridin-2-one, and1-(4-Amino-3-fluorophenyl)-5-methyl-1H-pyridin-2-one.
 2. A compoundaccording to claim 1 that is:1-(4-Amino-3-fluorophenyl)-1H-pyridin-2-one.